Volunteer for NIAID-funded clinical studies related to immune tolerance on ClinicalTrials.gov.
The immune system is precisely tuned to distinguish biochemical structures that belong to the body from those that do not, allowing it to swiftly deploy a potent array of defense mechanisms whenever evidence of a foreign invasion is found. However, many conditions, including autoimmune disorders, allergic diseases, and transplant rejection, are caused by inappropriate immune system responses.
To fight these disorders, researchers are now building on two decades of intensive basic research in immunology to develop treatments that can induce the immune system to tolerate specific antigens.
Progress in the development of these therapies, which have the potential to be both very potent and broadly applicable, has been very encouraging.
Click the text below to find or hide additional information.
All tolerance-induction strategies share a common goal: to selectively prevent or diminish specific harmful immune responses without disabling the immune system as a whole.
NIAID supports a wide range of programs to turn the promise of immune tolerance therapies into reality. Many of these are carried out by NIAID’s Division of Allergy, Immunology, and Transplantation (DAIT), which supports basic research into the mechanisms responsible for immune tolerance, translational research to facilitate the application of immune-tolerance approaches to human diseases, and clinical research to evaluate new therapies that can induce and maintain immune tolerance.
New approaches are being investigated to
In collaboration with the National Institute of Diabetes and Digestive and Kidney Diseases, DAIT supports the Nonhuman Primate Transplant Tolerance Cooperative Study Group (NHPCSG). The goal of this program is to evaluate the safety and efficacy of novel tolerogenic regimens in preclinical models of kidney and islet transplantation. Scientists in this study group have demonstrated long-term graft acceptance using tolerogenic regimens in both kidney and islet allograft recipients.
In FY 02, this program was expanded from 3 to 10 research grants. This expansion has allowed a larger number of tolerance-induction strategies to be rigorously evaluated, allowed the sharing of valuable resources, and facilitated the development of new collaborations. In FY 05, NHPCSG further expanded to include heart and lung transplantation. To accelerate research conducted through this program, DAIT maintains breeding colonies of specific pathogen-free rhesus and cynomolgus macaques.
Other DAIT-supported research programs that include studies on immune tolerance are the Autoimmunity Centers of Excellence, Innovative Grants on Immune Tolerance, and program projects in basic biology, basic immunology, and transplantation tolerance.
NIAID, along with the National Institute of Diabetes and Digestive and Kidney Diseases and the Juvenile Diabetes Research Foundation International, cosponsors the Immune Tolerance Network (ITN), an international consortium of more than 80 investigators in the United States, Canada, Europe, and Australia dedicated to the clinical evaluation of novel, tolerance-inducing therapies for autoimmune diseases, asthma and allergic diseases, and transplant rejection. ITN conducts integrated studies on the mechanisms that underlie immune tolerance and develops markers and assays to measure the induction, maintenance, and loss of tolerance in humans. The network has established several state-of-the-art core facilities and has supported 18 approved clinical protocols as well as several additional studies of the immune mechanisms involved in tolerance.
ITN is currently involved in the following areas of clinical research:
Examples of active ITN clinical research studies include:
Tolerance assays—tests and procedures to monitor patient responses to tolerance therapies—are critically needed to better evaluate tolerance-inducing therapies during and after clinical trials. ITN has therefore established a set of core laboratories to develop assays for the induction, maintenance, or loss of immune tolerance. These core facilities carry out microarray analyses of gene expression, develop analytic tools for clinical and scientific datasets from ITN-sponsored trials, and conduct enzyme-linked immunospot (ELISPOT) assay analyses of protein expression and cellular assays for T cell reactivity.
Examples of current ITN efforts to develop mechanistic assays include:
More information on ITN’s mission and research is available at www.immunetolerance.org.
The past two decades of intensive and highly productive research on the immune system have resulted in a wealth of new information and extraordinary growth in conceptual understanding. These accomplishments now provide realistic opportunities for major advances in the diagnosis, prevention and treatment of a broad range of human diseases involving the immune system. Significant advances over the past ten years include the identification of mechanisms by which antigen-specific immune tolerance can be induced to prevent pathologic immune responses. Based on the more comprehensive knowledge of immune tolerance that is now available, clinical applications to immune-mediated disorders are being developed, and early clinical trials are already in progress. The potential impact on human health is great, encompassing a wide range of immune-mediated disorders, including: autoimmune diseases, such as type 1 diabetes mellitus, multiple sclerosis, and systemic lupus erythematosus; asthma and allergic diseases; and graft rejection in solid organ, tissue and cell transplantation. Advances in tolerance induction will provide valuable new therapeutic strategies that do not require life-long, globally immunosuppressive therapy with its associated deleterious side effects, and the ability to modulate tolerance will also be important for preventing immune unresponsiveness to vaccines for tumors and infectious diseases.
In the fall of 1997, the National Institute of Allergy and Infectious Diseases (NIAID) began a scientific planning process to determine how best to capitalize on the extraordinary opportunities now available. The NIAID Plan for Research on Immune Tolerance was formulated to provide a conceptual framework and broad-based set of strategies to further our understanding of immune tolerance and to accelerate the clinical application of tolerogenic approaches to treat and prevent many immune-mediated diseases. I am grateful to the members of the NIAID Expert Panel on Immune Tolerance for providing the insights and guidance necessary to develop fully a meaningful long-range strategic plan. I also want to express appreciation to the members of the NIAID Expert Panel on Ethical Issues in Clinical Trials of Transplant Tolerance for their valuable recommendations on many of the ethical issues surrounding the use of tolerance induction therapy in the transplant setting.
We enter the next century with a solid foundation for expanding fundamental research and for translating basic knowledge into clinical applications. The challenges will be many, but the potential benefit for human health will be extraordinary.
Anthony S. Fauci, M.D.
National Institute of Allergy and Infectious Diseases
Report of the NIAID Expert Panel on Immune Tolerance
In February 1998, the National Institute of Allergy and Infectious Diseases (NIAID) convened a group of experts to review the Institute's plan for accelerating research on immune tolerance. Leading investigators in basic and clinical immunology provided recommendations on a long-range, broad-based plan encompassing basic, pre-clinical and clinical research as well as the development of important research resources.
This report summarizes: (1) the NIAID's overall scientific approach to facilitating research in this area; (2) the issues and questions addressed by the Expert Panel; and (3) the Panel's recommendations.
As the leading NIH Institute for research in immunology, the NIAID is in a unique position to capitalize on advances in basic, pre-clinical and clinical research aimed at achieving immune tolerance for immune-mediated diseases such as autoimmune and allergic diseases as well as transplant rejection. The NIAID's research plan is designed around a mechanism-based approach, rather than a disease-oriented approach, focusing on immune tolerance as the overall scientific framework and clinical objective. A major goal of this approach is to establish a collaborative and coordinated research effort involving basic immunologists, clinical researchers, relevant NIH Institutes, and the pharmaceutical and biotechnology industry. This will be accomplished by:
The Expert Panel addressed the following broad issues and questions:
The Expert Panel made the following specific recommendations concerning some of the key components of the research plan:
Abul Abbas, M.D., Professor, Department of Pathology, Brigham & Women's Hospital
Hugh Auchincloss, M.D., Associate Professor of Surgery, Harvard Medical School
K. Frank Austen, M.D., Director, Inflammation and Allergic Disease Research Section, Brigham & Women's Hospital
Jeffrey Bluestone, Ph.D., Professor, Ben May Institute of Cancer Research, University of Chicago
Charles Carpenter, M.D., Professor, Department of Medicine, Brigham & Women's Hospital
Leonard Chess, M.D., Professor, Department of Medicine, Columbia University
Joseph Davie, M.D., Ph.D., Vice President, Department of Research, Biogen, Inc.
C. Garrison Fathman, M.D., Professor, Department of Medicine, Stanford University
Maureen Howard, Ph.D., Vice President, Research, Anergen, Inc.
Jean-Pierre Kinet, M.D., Professor, Beth Israel Deaconess Medical Center, Harvard Medical School
Allan Kirk, M.D., Ph.D., Senior Investigator, Naval Medical Research Institute
Lee Nadler, M.D., Professor, Department of Medicine, Dana-Farber Cancer Institute
Megan Sykes, M.D., Associate Professor, Transplantation Biology Research Center, Massachusetts General Hospital
Laurence Turka, M.D., Associate Professor, University of Pennsylvania
Recommendations of the NIAID Expert Panel on Ethical Issues in Clinical Trials of Transplant Tolerance
In April 1998, the National Institute of Allergy and Infectious Diseases (NIAID) convened an expert panel to begin developing guidelines for the design, conduct and monitoring of scientifically and ethically acceptable clinical trials to evaluate the safety and efficacy of new approaches to achieve immune tolerance in transplant recipients. A group of experts in bioethics, law and basic and clinical research in transplantation joined NIH staff and representatives of the Food and Drug Administration and the NIH Office of Protection from Research Risks.
Transplantation is now routine therapy for end-stage renal disease, with one-year graft survival approaching 90% using standard immunosuppressive therapy. However, long-term graft survival has not improved appreciably since the early 1980s and only about 45% of cadaveric kidneys survive ten years post-transplant. For other organs (e.g., liver, lung and pancreas), graft survival does not approach this level. While new immunosuppressive drugs have reduced acute rejection in the first year post-transplant, it is clear that these therapeutic improvements will not significantly alter long-term clinical outcomes. Therefore, much recent attention has focused on the potential for the induction of donor-specific immune tolerance to achieve long-term graft survival without the need for non-specific, life-long immunosuppressive therapy that has deleterious and often life-threatening side effects. Although certain promising tolerogenic molecules have been shown to induce donor-specific tolerance in rodent and non-human primate transplant models and are being tested in humans for the treatment of selected autoimmune diseases, these approaches have not been evaluated for transplantation in humans.
A major ethical dilemma in moving forward with clinical trials for the induction of transplant tolerance results from the growing body of knowledge that standard immunosuppressive therapy blocks the intracellular signals necessary to induce at least some types of tolerance. Therefore, transplantation clinical trials to evaluate the safety and efficacy of tolerogenic approaches will involve withholding standard immunosuppressive therapy or significantly altering immunosuppressive regimens.
The expert panel was asked to address a number of critical questions and issues, including the following:
The panel acknowledged that clinical trials of tolerance induction in the transplant setting is a rapidly evolving field of investigation that will require ongoing review by a similar panel of experts. The risks and benefits associated with decisions to initiate human studies and the design and monitoring of human studies should be reviewed on a case-by-case basis by experts in bioethics, law and basic and clinical research in transplantation.
Charles B. Carpenter, M.D., Professor of Medicine, Brigham and Women's Hospital, Harvard University
James Childress, Ph.D., Kyle Professor of Religious Studies, Professor of Medical Education and Chairman, Department of Religious Studies, University of Virginia
David Essayan, M.D., Medical Officer, Pharmacology & Toxicology Branch, Division of Clinical Trials Design and Analysis, Office of Therapeutics Research and Review, Center for Biologics Evaluation and Research, Food and Drug Administration
Norman Levinsky, M.D., Associate Provost and Professor of Medicine, Boston University Medical Center
Bernard Lo, M.D., Professor of Medicine, University of California, San Francisco
Louis Marzella, M.D., Ph.D., Medical Officer, Pharmacology & Toxicology Branch, Division of Clinical Trials Design and Analysis, Office of Therapeutics Research and Review, Center for Biologics Evaluation and Research, Food and Drug Administration
Lee Nadler, M.D., Chairman, Department of Adult Oncology, Division of Hematologic Malignancies, Dana Farber Cancer Institute
Philip D. Noguchi, M.D., Director, Division of Cellular and Gene Therapies, Center for Biologics Evaluation and Research, Food and Drug Administration
Thomas Pearson, M.D., Associate Professor, Department of Surgery, Transplant Immunology, Emory University
Harold Y. Vanderpool, Ph.D., Th.M., Professor in the History of Philosophy, Institute for Medical Humanities, University of Texas Medical Branch
Robert Veatch, Ph.D., Professor of Medical Ethics and Senior Research Scholar, Kennedy Institute of Ethics, Georgetown University
Alison Wichman, M.D., Deputy Director, Office of Human Subjects Research, Office of Intramural Research, National Institutes of Health
Mohamed H. Sayegh, M.D., Director, Laboratory of Immunogenetics and Transplantation Research, Brigham and Women's Hospital, Harvard University
Terry Strom, M.D., Professor of Medicine, Division of Immunology, Beth Israel Deaconess Medical Center
Judy Massicott-Fisher, Ph.D., Health Scientist Administrator, Division of Heart and Vascular Diseases, National Heart, Lung and Blood Institute
Kamal Mittal, Ph.D., Northwest and Compliance Coordinator, Office of Protection from Research Risks, Office of the Director, National Institutes of Health
Camille A. Jones, M.D., MPH, Epidemiology Program Director, Division of Kidney, Urology and Hematology, National Institute of Diabetes and Digestive and Kidney Diseases
Robert Goldstein, M.D., Ph.D., Vice President of Research, Juvenile Diabetes Foundation International
Part 1: Overview
As the leading NIH Institute for research in immunology, the NIAID is in a unique position to capitalize on advances in basic, pre-clinical and clinical research focused on achieving immune tolerance for immune-mediated diseases, including autoimmune and allergic diseases as well as transplant rejection. This research plan provides a broad-based set of strategies and initiatives to further our understanding of immune tolerance and to accelerate the clinical evaluation of tolerogenic approaches to treat and prevent immune system diseases.
The plan provides an effective model for translational research and for ensuring that key studies are performed in a coordinated and efficient manner. The plan is designed around a mechanism-based (as opposed to a disease-oriented) approach, focusing on immune tolerance as the overall scientific framework and clinical objective. The goal is to begin a more collaborative and coordinated research effort-one involving basic immunologists, relevant clinical specialties, other NIH Institutes and the pharmaceutical and biotechnology industry. Major features of the plan are outlined below.
Part 2: Background
Normal immune activation is the greatest barrier to graft survival in allogeneic organ, cell and tissue transplantation. Most protocols in transplantation and autoimmune diseases include globally immunosuppressive agents which are associated with increased risks of infection and neoplasia. Given such serious side effects, major research efforts to avoid the complications of immunosuppressive drugs are amply justified. One very attractive alternative is to redirect the immune system to establish antigen-specific tolerance to transplant antigens or to restore normal self-tolerance in autoimmune diseases.
Tolerance is defined here as a selective block in the immune response to particular antigens. Methods of tolerance induction include: 1) the deletion or specific inactivation (anergy) of antigen-reactive lymphocytes; 2) altering profiles of cytokine secretion to prevent inflammation and injury; and 3) preferential induction of regulatory T cells or cytokines that inhibit destructive T cell functions. In animal models, these approaches have resulted in long-lasting, antigen-specific nonresponsiveness.
A solid experimental foundation already exists and many unique reagents are now available to support translational research and pursue promising clinical applications. The potential impact for human health is great, encompassing all allergic and immune-mediated diseases, allograft rejection, graft-versus-host disease, and responses to "neoantigens" introduced via gene therapy.
A major area of interest is the induction of tolerance by preventing costimulatory second signals. It is now well established that lymphocyte activation requires two signaling events. Signal-one is triggered by antigen presentation through the T cell receptor (TCR) and signal-two involves cognate interactions between costimulatory molecules on antigen presenting cells and lymphocytes. Propagation of signal-one in the absence of signal-two inactivates or tolerizes the responding lymphocyte. Second-signal blockade ultimately results in either death or anergy of the responding cell.
For T cells, blockade can be accomplished by antibodies or engineered soluble receptors that bind to costimulatory ligands to prevent normal T cell activation and divert the response to tolerance. The major costimulatory signal studied thus far is initiated by CD28:B7 interactions, which can be prevented by antibodies to B7 or by a soluble form of the CTLA4 receptor protein (CTLA4-Ig) that binds B7 with high affinity. Other costimulatory targets include a T cell molecule called CD40-ligand (CD40-L), which normally induces B7 expression by binding CD40 on antigen-presenting cells. Both CTLA4-Ig and anti-CD40-L antibodies were found to induce long-term tolerance when given during kidney transplantation in mice and in rhesus monkeys, and to induce tolerance in some murine models of autoimmune disease. The great advantage of this approach is that CTLA4-Ig or anti-CD40-L antibody treatment is required only during the initial exposure to antigen. Thereafter, grafts are retained or autoimmune disease is prevented in most cases without subsequent treatment of any kind. In those cases where transplant tolerance ultimately breaks down, a "rejection-free" state has been restored by a second course of CTLA4-Ig or anti-CD40-L antibody.
Additional agents should also be tested, such as those that target the costimulatory molecules, CD2, CD30 or 4-1BB, target adhesion molecules such as ICAM or VLA, or interrupt intracellular signaling pathways necessary for T cell activation, such as ZAP-70. Combinations of these reagents may also be useful to induce more robust and durable tolerance.
Further development is needed for approaches that induce lymphocyte death upon antigen recognition. Although much has been learned about activation-induced cell death, tolerance due to cell death has been verified in only a few systems in vivo. Given the recent explosion of information on the molecules and signaling pathways responsible for the induction or prevention of apoptosis, it is likely that methods can be developed to specifically target disease-associated lymphocytes for death via antigen recognition. Examples of this approach include expression of recombinant Fas-ligand on tissue to kill infiltrating T cells and the use of anti-IL-2 receptor antibodies to eliminate activated T cells.
A third major focus is cytokine modulation to prevent destructive immune responses. In general, cytokines that promote inflammatory conditions, such as IFNß, TNFß and LT, will promote graft rejection and T cell-mediated autoimmune attacks, whereas those that are anti-inflammatory, such as IL-10 and TGFß, will promote autoantibody production, but may alleviate graft rejection and suppress inflammatory autoimmune attack. The mechanisms responsible for the destructive immune response must be determined before cytokine modulation is applicable, and the feasibility, safety and efficacy of cytokine modulation in man must be assessed. Important issues include systemic versus local cytokine delivery, synergistic or antagonistic effects, and the possibility of replacing one type of immune response with another type that is still destructive.
Additional approaches include a focus on the migration of activated lymphocytes which might be blocked to prevent tissue damage, on anti-CD3 antibody or other reagents that are coupled with toxins to selectively destroy activated T or B cells, and on molecularly engineered tissues that would delete or inactivate tissue-infiltrating lymphocytes. Peptide-based therapies might be effective when the specific antigens are known, since altered peptide analogues might induce tolerance. Furthermore, peptides derived from T cell antigen receptors (TCR) have been shown in some systems to induce regulatory T cells that recognize and inhibit the TCR+ disease-mediating effector cells.
Transplantation is now routine therapy for end-stage renal disease, with one-year graft survival approaching (85% using current immunosuppressive therapy. However, long-term graft survival has not improved appreciably since the early 1980s, with approximately 45% of cadaveric kidneys surviving at 10 years post-transplant. For other organs (e.g., liver, lung, and pancreas), graft survival does not approach this level of success. While new immunosuppressive drugs are reducing acute rejection in the first year post-transplant, it is increasingly clear that these therapeutic improvements will not significantly alter long-term clinical outcomes. Therefore, much recent attention has focused on the potential for the induction of donor-specific immune tolerance to achieve long-term graft survival without the need for non-specific immunosuppressive therapy.
A major ethical dilemma in moving forward with clinical trials for the induction of transplant tolerance results from the growing body of knowledge that standard immunosuppressive therapy blocks intracellular signals necessary for at least some types of tolerance induction. Therefore, evaluating the safety and efficacy of tolerogenic approaches will require withholding standard immunosuppressive therapy. Although certain promising tolerogenic molecules are being tested in humans for the treatment of some autoimmune diseases, and have been shown to induce donor-specific tolerance in rodent and non-human primate transplant models, these approaches have not been evaluated in transplantation clinical trials.
In April 1998, the NIAID convened an expert panel to begin developing guidelines for the design, conduct and monitoring of scientifically and ethically acceptable clinical trials of the safety and efficacy of new tolerance induction approaches in transplant recipients. A group of experts in bioethics, law and basic and clinical research in transplantation joined NIH staff and representatives of the Food and Drug Administration and the NIH Office of Protection from Research Risks. The recommendations of this expert panel will be incorporated into NIAID-sponsored clinical trials of tolerance induction in the transplant setting.
Part 3: Detailed Research Plan
Solid organ and cell transplantation provide fertile ground for the evaluation of strategies to achieve tolerance. Since much of the pre-clinical work on immune tolerance has focused on kidney and islet transplantation, these two areas of investigation hold the most promise for moving research into the clinical setting. NIAID's established leadership role in kidney transplantation clinical trials and the availability of a cooperative infrastructure for evaluating tolerogenic approaches provide a compelling rationale for studies in kidney transplantation. Importantly, this cooperative effort has identified sensitive early predictors of rejection which can be readily quantified in peripheral blood and urine. In the case of islet transplantation, engraftment and one-year graft survival are poor (less than 5% insulin independence at one year) even with aggressive non-specific immunosuppression. Hence, there is a clear need to develop new approaches including the induction of donor-specific tolerance. Furthermore, NIAID currently supports a highly qualified cadre of investigators whose work is already focused on tolerogenic approaches relevant to kidney and islet transplantation. Finally, from an ethical standpoint, the availability of "rescue" therapies (hemodialysis and insulin therapy) for both kidney and islet transplant recipients will facilitate clinical evaluation.
Kidney Transplantation: Specific Initiatives
Kidney Transplantation: Detailed Research Plan
Development and evaluation of tolerogenic approaches in kidney transplantation will require a phased approach to provide adequate data for the design of efficacy trials without standard immunosuppression. This plan includes: (1) non-human primate studies to refine tolerogenic regimens and provide for longer-term assessements of efficacy alone and in combination with immunosuppressive therapy; (2) further definition of the mechanisms of action of these experimental treatments; (3) development of effective monitoring strategies, including methods to demonstrate the induction or loss of immune tolerance in humans; (4) pilot clinical trials of safety and potential efficacy; and (5) multi-center efficacy trials.
Non-Human Primate Studies and Pilot Clinical Trials
The plan focuses on unsolicited and solicited research and involves NIAID staff working closely with investigators and pharmaceutical and biotechnology companies to identify promising projects. Two specific projects under development are outlined below, and additional opportunities in this area are being pursued.
Research conducted by the Naval Medical Research Institute provides a foundation for advancing our understanding of immune tolerance in kidney transplantation. These studies should be expanded to provide the data necessary for the design of pilot clinical trials and should include: (1) additional studies of anti-CD40 ligand antibody, alone and in combination with various single immunosuppressive agents, in monkeys with MHC-mismatched kidney transplants; (2) evaluation of the effect of administration of donor bone marrow cells at the time of anti-CD40 ligand antibody treatment to determine if the presence of donor cells extends the ability to maintain long-term tolerance; (3) studies of underlying mechanisms and markers of tolerance in these monkey models; and (4) pilot clinical trials of safety and potential efficacy. Support will also be important for studies of second generation agents, such as high affinity anti-CD40 ligand antibody, to evaluate whether reduced doses of such molecules can induce tolerance in fully mismatched kidney transplants in a monkey model.
Other studies show promising preliminary results, including a pilot clinical study of a humanized, non-activating anti-CD3 antibody for reversal of acute kidney rejection. Such efforts should be expanded for both reversal of rejection and tolerance induction. Furthermore, additional strategies are worthy of investigation, including the use of bone marrow or purified stem cells to deliver tolerogenic signals and gene transfer approaches for the delivery of immunomodulatory agents.
Expansion of the NIAID Cooperative Clinical Trials in Adult Kidney Transplantation
The development of tolerogenic treatment strategies will require the capacity to conduct multi-center clinical trials. The NIAID Cooperative Clinical Trials network in adult kidney transplantation, established in 1991 and currently composed of 52 participating sites, can provide the infrastructure necessary to evaluate the safety and efficacy of promising approaches to achieve and maintain tolerance in kidney transplant recipients. An expansion of this cooperative research program will provide the resources necessary to conduct Phase I, II and III clinical trials within the existing sites and to expand the number of participating sites to ensure an adequate accrual for all phases of clinical investigation. Based on the results of studies in adults with respect to safety, toxicity and proof of concept, clinical trials in pediatric kidney transplant recipients can be initiated. This expanded clinical research program will be supported by the Human Immunology Cooperative Study Groups to standardized immune markers of tolerance induction and maintenance, study mechanisms of action of various tolerogenic therapies, and develop improved methods to detect and predict acute and chronic rejection.
Prospective Registry of Kidney Transplant Recipients
Establishment of an NIAID-supported registry and repository will provide the stable infrastructure necessary to collect recipient and donor samples and conduct relevant studies of long-term clinical outcomes.
Islet transplantation seeks to restore pancreatic beta cell function by replacing the pancreatic insulin-producing cells destroyed by immune-mediated injury in type 1 diabetes mellitus. The ultimate goal is to provide a sufficient number of functioning islets to achieve normal insulin production and secretion and to prevent the serious renal, neurologic and vascular complications of this disease. In patients with type 1 diabetes mellitus, fewer than 5% of those receiving islet transplants in conjunction with aggressive immunosuppressive therapy remain insulin-independent at one year. This poor outcome could be the result of recurring autoimmune destruction or immune rejection. Furthermore, the immunosuppressive agents themselves are responsible for at least some of this destruction. These sobering results highlight the importance of developing other approaches to ensure successful engraftment, survival and normal function. Furthermore, islet transplantation is an exceptional clinical setting to test tolerance induction protocols since transplant failure is not life-threatening and patients can be returned to insulin therapy without detrimental long-term consequences. In addition, islet transplantation will provide valuable new information on the ability to induce tolerance in the context of an underlying autoimmune disease.
Most research in this area is being conducted in rodent models, with some promising studies in non-human primates, and a small but evolving effort in human islet transplantation. The immunologic hurdles are considerable and overcoming them will require additional investments in basic, pre-clinical and clinical research. The major areas in need of further investigation include:
Islet Transplantation: Specific Initiatives
Islet Transplantation: Detailed Research Plan
Non-Human Primate Studies
The approach to advancing investigations in non-human primate models of islet transplantation focuses on unsolicited research and involves NIAID staff working closely with investigators and pharmaceutical and biotechnology companies to identify promising studies and tolerogenic approaches. Two specific projects are described below and additional opportunities will be pursued.
Recently published results by an NIAID grantee highlight the potential for achieving long-term graft survival using an anti-CD3 immunotoxin molecule in a monkey model of kidney transplantation. This work is now being extended to islet transplantation in a newly identified and unique population of rhesus monkeys with spontaneous diabetes mellitus. Preliminary results indicate that the immunotoxin-treated animals remain insulin-independent with none of the usual complications of this disease. Furthermore, reconstitution of general immune function has been demonstrated. Such non-human primate studies should be expanded to provide the data necessary to design pilot clinical trials of safety and potential efficacy.
In addition, the promising results from the Naval Medical Research Institute study of anti-CD40 ligand antibody for kidney transplantation are being extended to islet transplantation. Preliminary investigations of the use of this molecule in baboons have been conducted by the Diabetes Research Institute at the University of Miami. Results from these early efforts show that anti-CD40 ligand antibody is able to prevent islet destruction post-transplant and recurrent autoimmune destruction of the transplanted cells. Similarly, additional studies of this co-stimulatory blockade approach, as well as other strategies, merit further investigation in non-human primates and man. Other approaches include: (1) the use of a humanized, non-activating anti-CD3 antibody for tolerance induction in non-human primates; (2) further evaluation of anti-CD40 ligand antibody; and (3) studies of CTLA4-Ig and anti-B7 antibodies.
NIAID Cooperative Clinical Trials in Islet Transplantation
The small but growing effort to study immune tolerance in human islet transplantation consists primarily of individual pre-clinical and pilot clinical studies under industry sponsorship with little NIH involvement. Advances in this area will require the capacity to design and conduct standardized protocols at multiple sites. Therefore, the establishment of a program for cooperative clinical trials in islet transplantation will provide the infrastructure and the clinical and basic science expertise necessary for more rigorous and standardized evaluations of safety and efficacy. This new clinical network will be supported by the Human Immunology Cooperative Study Groups for investigations of mechanisms of action, improved methods to detect and predict rejection, as well as standardization of immune markers of tolerance induction and maintenance.
Developmental/Exploratory Research Projects and Small Business Innovative Research (SBIR) Grants
Progress in islet transplantation is impeded by both immunologic and non-immunologic limitations. Two of the most critical obstacles include procuring sufficient numbers of islets and the immune destruction of transplanted beta cells.
Research to date has relied on the procurement of islets from cadaveric donors-a severely limited source of cells suitable for transplantation. Other largely under-explored beta cell replacement strategies include beta cells grown in culture to expand the number available for transplantation and bioengineering strategies encompassing: the production of non-beta cells transfected with genes and regulatory elements to mimic beta cell function, and human beta cells engineered to enhance engraftment and/or prevent rejection. Progress in this area will require research to determine those functional beta cell components necessary for glucose-regulated insulin secretion, including the internal beta cell machinery, interactions among beta cells, and interactions between beta cells and the extracellular milieu.
Pre-clinical and clinical research in islet transplantation have revealed an early, primary destruction of transplanted cells by both immune and non-immune mechanisms which are, to date, largely undefined. One approach to prevent the immune destruction involves isolation of the transplanted cells from the immune system and is being pursued by NIAID and the pharmaceutical and biotechnology industry. There are several methods to achieve isolation, including: implantation in an immune-privileged site; encapsulation in an immune protective membrane; and co-transplantation of beta cells with, for example, transfected myoblasts secreting agents (TNF or Fas-L) to induce apoptosis of the invading cytotoxic lymphocytes. Exploratory research in this area merits further development.
Part 3: Detailed Research Plan
B: Autoimmune Diseases
Efforts to induce tolerance in autoimmunity have focused primarily on the oral administration of antigens. Oral administration of both high-and-low dose antigen results in a phenomenon termed "oral tolerance" in which the immune response to subsequent systemic administration of antigen is blocked. Oral tolerance can be induced in animal models and is now being evaluated in human diseases. However, the encouraging responses in animal studies have not been duplicated in recent clinical trials of rheumatoid arthritis and multiple sclerosis. A clinical trial of oral insulin comprises one limb of the NIH-sponsored Type 1 Diabetes Prevention Trial (DPT-1). Results of this large clinical trial, which also includes low-dose parenteral insulin for at-risk nondiabetic relatives of individuals with type 1 diabetes mellitus, will not be available for several years. However, there are a number of promising tolerogenic approaches other than oral tolerance that can now be pursued in immune-mediated diabetes and other autoimmune diseases. These include: co-stimulatory blockade; anti-cytokine monoclonal antibodies; hematopoietic stem cell and bone marrow transplantation; and gene transfer-based therapies for cytokine modulation.
These approaches will require extensive collaborations among basic immunologists and clinical investigators from many specialties. Therefore, a major thrust of the research initiatives in this area focuses on the establishment of cooperative research programs capable of incorporating the basic science and clinical expertise necessary to accelerate progress.
The rationale for initiating pilot clinical trials is based on multiple factors. First, several mouse studies have indicated that co-stimulatory blockade (e.g., anti-CD40 ligand or CTLA4-Ig antibody treatment) can reverse experimental autoimmune disease. Second, very few non-human primate models of human autoimmune disease exist and the models that do exist have not proved useful for pre-clinical evaluation of therapeutic approaches. Finally, studies in humans are already underway under the sponsorship of several pharmaceutical and biotechnology companies.
Individual pilot clinical trials of the safety and potential efficacy of tolerogenic molecules/reagents.
Establishment of a Cooperative Clinical Trial Group for the study of immune tolerance in autoimmunity.
Pilot Clinical Trials
Support for pilot clinical trials to evaluate the safety and potential efficacy of promising tolerogenic approaches will be the initial phase of development. Investigators are currently developing pilot clinical studies to delay disease progression for newly diagnosed type 1 diabetics and in diabetic patients refractory to standard therapy. In addition, industry and some individual investigators are targeting systemic lupus erythematosus, rheumatoid arthritis, and multiple sclerosis. Clinical trials underway include:
Examples of the research being carried out at present include Biogen's ongoing work with anti-CD40 ligand antibody for the treatment of Idiopathic Thrombocytopenia Purpura (ITP) and lupus nephritis. ITP is a T cell-dependent, antibody-mediated autoimmune disease in which platelets are destroyed. Two-thirds of ITP patients are cured by splenectomy, but one-third are refractory to this aggressive treatment and remain chronically at risk for life-threatening hemorrhage, especially in the central nervous system. The rationale underlying this therapeutic approach is the ability of anti-CD40 ligand antibody to regulate T cell-dependent antibody production. In addition, the endpoints for therapeutic response are readily discernable, i.e., a rise in platelet counts and decreases in titers of anti-platelet antibodies and in the number of transfusions required. Research of this type offers the opportunity to: study mechanisms of disease amelioration; determine the effects of anti-CD40 ligand antibody on autoantibody production; and examine the potential application of this therapy for other T cell-dependent, antibody-mediated autoimmune diseases, such as systemic lupus erythematosus.
Biogen has promising preliminary results from studies of anti-CD40 ligand antibody in mice with lupus nephritis, also a T cell-dependent, autoantibody-mediated autoimmune disease. This treatment prevented the onset of disease and, in mice with advanced lupus nephritis, has produced a dramatic increase in survival and a decrease in proteinurea. In addition, the treatment has resulted in a partial reversal of the normally severe glomerular injury characteristic of this disease. Testing safety and potential efficacy in humans will be the next step in the development of this molecule and, if successful, could pave the way for its use to treat and prevent other complications of this disease, e.g., neurologic, rheumatologic and hematologic.
In other autoimmune diseases, interactions between antigen-presenting cells and T cells produce inflammatory molecules responsible for tissue, nerve and organ damage. One promising therapeutic approach involves interrupting or preventing these interactions. Two products, developed by Anergen Inc., are being evaluated in clinical trials of multiple sclerosis and rheumatoid arthiritis. AnergiX uses specific self-peptides, complexed with soluble Major Histocompatibility Complex (MHC) class II molecules, to stimulate disease-specific T cells in the absence of a co-stimulatory signal. As a result, specific T cells are inactivated and no longer produce inflammatory molecules. Pilot clinical trials are underway and preliminary results are promising.
The second product, AnervaX, is based on the same principle, but does not require knowing the identify of the disease-causing autoantigen. AnervaX exploits the strong MHC-linkage of many autoimmune diseases by vaccinating with an immunodominant epitope of the disease-linked MHC molecules to induce a host-immune response which blocks subsequent antigen presentation by those molecules to disease-causing autoreactive T cells. As a result, the T cell is not activated, no inflammatory mediators are produced, and disease is prevented. Phase II trials for rheumatoid arthritis are underway and appear promising.
NIAID Cooperative Clinical Trial of Immune Tolerance for Autoimmune Diseases
The NIAID Cooperative Clinical Tnamerial of Immune Tolerance for Autoimmune Diseases will design and conduct efficacy studies in type 1 diabetes, multiple sclerosis, rheumatoid arthritis and systemic lupus erythematosus, with all studies incorporating investigations of underlying mechanisms. A cooperative approach has many important strengths. The multi-site infrastructure will ensure that adequate numbers of patients are available for clinical trials. This is particularly important for the many autoimmune diseases which afflict only a small proportion of the population. In addition, such a network promotes the participation of multiple clinical specialties relevant for autoimmune disease and collaboration among clinical and basic scientists to further understanding of the underlying immune mechanisms. A cooperative research program will also enable the participation of multiple NIH Institutes with responsibility for research on specific autoimmune diseases and aid in bringing together the clinical investigators supported by other NIH components and the basic immunology community within NIAID's portfolio. As noted above, several pharmaceutical and biotechnology companies and individual investigators are already pursuing pre-clinical and clinical research on immune tolerance in autoimmunity and the potential for collaborative efforts is promising.
Current NIAID efforts to develop collaborations with companies for pilot clinical trials will lay the groundwork for cooperative, multi-site Phase II and III clinical trials using this infrastructure. In addition, the participation of other NIH Institutes will be encouraged and pursued.
Part 3: Detailed Research Plan
C: Asthma and Allergic Diseases
Asthma and allergic diseases are attractive models for development of new approaches to alter the human immune response. These diseases are increasing in prevalence and account for high medical and social costs. Despite the availability of proven therapies and many new agents in development, even the most effective pharmacotherapies have serious limitations. Some data suggest that either reduced allergen exposure, or conventional allergen immunotherapy, can block the development of asthma and/or exacerbations of asthma. However, there are obstacles to translating these findings into clinical practice, perhaps because present approaches to environmental control do not sufficiently reduce allergen levels, and because conventional immunotherapy causes only weak modulation of the human immune response. The most promising approach is to develop new methods of inhibiting allergic immune responses and/or inducing tolerance to allergens.
The development of new approaches would be enhanced by the many widely available, well standardized and clinically validated tests, including blood studies, skin tests, and pulmonary function tests, that can be used to characterize allergic responses from the immunological and physiological perspectives. Moreover, it may soon be possible to enhance the identification and stratification of at-risk individuals based on the discovery of genes that predispose to asthma and atopy.
Allergen immunotherapy was developed empirically ~80 years ago and relatively little effort has been made to develop more robust and long-lasting allergen immunotherapies, based on fundamental principles of immunology. However, concerns about the efficacy of conventional immunotherapy have stimulated research into new approaches to tolerize to allergen. A variety of avenues are being explored and build on the fact that many clinically important allergens have been identified, purified, cloned, epitope-mapped, produced as biologically active recombinant proteins, and administered safely by mucosal and cutaneous routes. With these reagents, the timing, dose, route, and molecular form for the allergen can be tightly controlled. Approaches that combine non-antigen specific methods (e.g., second signal blockade and cytokine modulation) and antigen-specific tolerance appear very promising in animal models and are close to entering Phase I and/or Phase II clinical studies in man. Among these are: 1) "DNA vaccines" comprised of plasmid DNA encoding recombinant allergens, which induce long-lasting allergen-specific tolerance in mice; 2) immunostimulatory oligonucleotides, small sequences of bacterial DNA that drive the Th1 immune responses when co-administered with protein allergens; 3) T cell co-stimulatory blockade in conjunction with allergen challenge; 4) peptide vaccines representing T cell epitopes of allergen; 5) immunization with Mycobacterium vaccae, which non-specifically drives Th1 immune responses; 6) monoclonal antibodies to IgE, which deplete plasma IgE and down-regulate mast cells and basophil receptors for IgE; and 7) co-administration of allergen and cytokines.
NIAID Cooperative Clinical Trial in Allergen Immunotherapy
The establishment of a Cooperative Clinical Trial in Allergen Immunotherapy will provide the infrastructure to capitalize on current opportunities to evaluate tolerogenic approaches for the treatment of human allergic diseases. With such a program, standardized clinical trials at all phases would be carried out by clinical investigators in cooperation with basic immunologists to assess safety, efficacy, mechanisms of action, and therapeutic effect of multiple approaches, including second signal blockade, DNA, oligonucleotide and microbial adjuvants, and co-administration of cytokines. The Cooperative Clinical Trial in Allergen Immunotherapy would be linked to the Human Immunology Cooperative Study Groups to support basic and mechanistic studies of new allergen immunotherapies.
Multidisciplinary Research Centers in Asthma and Allergic Diseases
To facilitate future discovery, a network of Research Centers will be important for the development and testing of new reagents and approaches for tolerizing human allergic responses. The basic and translational research conducted by these Centers would span many disciplines (e.g., T and B cell immunology; antigen [allergen] processing and presentation; biology and function of mast cells, eosinophils, and basophils; high-resolution structural studies of allergens; and vaccinology) with the ultimate aim of discovering new tolerizing approaches. Shared resource cores (e.g., for the purification of allergens or for production and modification of recombinant allergens; for structural characterization of allergens; for production of DNA vaccines and other DNA-based therapies; and for testing experimental therapies in appropriate animal models) would serve all Research Centers in the network.
Part 3: Detailed Research Plan
D: Cross-Cutting Research
The establishment of Human Immunology Cooperative Study Groups is a critical component of this research plan and will provide the techniques and data essential for the design of immune tolerance protocols, including standardized assays and reliable markers of tolerance. The NIAID Cooperative Clinical Trial in Adult Kidney Transplantation has identified sensitive predictors of rejection and delineated some immunologic parameters involved in both rejection and graft survival. However, these results are still preliminary and additional resources will be required to: expand this line of investigation in transplantation, autoimmunity and allergic diseases; focus additional efforts directly on immune tolerance; and provide the cooperative infrastructure necessary to conduct research using common approaches and standardized techniques. This Group will serve as a central resource for studies conducted by the NIAID Cooperative Clinical Trials in Kidney Transplantation, Islet Transplantation, Autoimmune Diseases, and Asthma and Allergic Diseases, as well as clinical and non-human primate studies conducted by other NIAID grantees. Examples of research areas that might be supported include:
A joint Task Force on Transplantation Tolerance, convened by the American Society of Transplant Physicians (ASTP) and the American Society of Transplant Surgeons (ASTS), held its first meeting in October 1997. The goal of this joint effort is to develop guidelines and projects to facilitate the application of tolerogenic approaches in the transplant setting. The participants agreed on the importance of establishing an NIH-supported cooperative group to develop markers and assays for studies of human immune tolerance.
Translation of the basic immunological principles of tolerance to clinical applications will require greater coordination of research and resources than is currently in place. This will entail development of the appropriate infrastructure to facilitate investigator interactions and enable ready access to research resources. Specific components of the research plan include:
Good Manufacturing Practice Facility
A Good Manufacturing Practice (GMP) Facility will expand the availability of promising tolerogenic molecules and, in doing so, accelerate their evaluation in pre-clinical studies, clinical trials, and more fundamental investigations of mechanisms of action. Such a facility will ensure the timely availability of immunologically important materials for NIAID-supported investigators and will be important in advancing research on immune tolerance for several reasons. It will allow studies of mechanisms of action in cases where industry is unable or unwilling to pursue this line of investigation. In addition, it will permit the NIAID to sponsor further research in cases where industry has abandoned product development. For small companies, the costs of producing reagents is often prohibitive and, in other cases, preliminary discussions with industry suggest that licensing research materials to the NIAID may be contingent upon the Institute's capacity for further production. Finally, in many instances, an individual investigator lacks the resources to produce these materials in-house.
Mouse Breeding and Distribution
NIAID currently supports the importation, breeding and distribution of immunologically relevant, unique gene-knockout and transgenic mouse strains for the extramural research community. This program will be expanded to provide early access to additional mouse strains already developed as models for transplantation, autoimmune and allergic diseases, and to animals that will be useful for new model development. These may include "humanized" mice that express one or more human molecules, such as CD4, CD8, MHC I or II, to increase the similarities of mouse models to human disease, or mice that express genetically engineered co-stimulatory molecules or signal transduction components thought to play a role in the induction or maintenance of tolerance.
Breeding and Maintenance of Non-Human Primates
The breeding and maintenance of non-human primates can be supported efficiently through the seven Regional Primate Centers funded in part by the National Center for Research Resources (NCRR). In supporting these Centers, NCRR provides funds for administrative costs, the building and maintenance of facilities, and approximately 40 percent of staff salaries. Since a substantial portion of the costs associated with these Centers is already supported by NCRR, using these existing facilities would provide a more cost-efficient method for breeding and maintaining non-human primates for research on immune tolerance. Support can be provided from grant or contract funds and direct NIAID financing will eliminate the indirect costs associated with purchasing such services on the part of individual academic institutions.
Research Training Programs
Ensuring an adequate supply of well trained and highly qualified basic scientists and clinical researchers is an important aspect of the ability to continue to accelerate research in this area. Training needs are particularly critical for translational research, underlying mechanism studies, and the design and conduct of clinical trials. New clinical training programs recently established by the NIH Director will be used to provide career development support in these areas. Additional opportunities will be pursued, including the incorporation of career development support within some of the research programs to be established.
Establishment of an innovative research grant program will provide short-term support for a variety of pilot projects to establish truly novel areas of immune tolerance research. The objective of this program is to produce preliminary data that validate innovative but, as yet, speculative tolerance concepts or clinical feasibility in basic, pre-clinical or clinical areas of tolerance research. Successful grants will provide the foundation for future projects to be pursued using conventional funding mechanisms. It is expected that this program will broaden the base of scientific discovery by encouraging the rapid development of new ideas and by attracting investigators previously outside the tolerance field.
Examples of specific areas of research to be supported by this program include:
Support for multidisciplinary projects will expand knowledge of the molecular basis for tolerance induction and maintenance in animal and human systems. Examples of the types of research to be supported include:
Last Updated September 30, 2013
Last Reviewed October 18, 2010