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NIAID Plan for Research on Immune Tolerance

Part 3: Detailed Research Plan

A: Transplantation

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

Kidney Transplantation: Specific Initiatives

  • Expansion of research in non-human primate models followed by pilot clinical trials.

  • Expansion of the NIAID Cooperative Clinical Trial in Adult Kidney Transplantation to conduct multi-center efficacy trials.

  • Establishment of a prospective registry of kidney transplant recipients and a repository of tissue and blood samples.

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 Transplatation

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:

  • Identification of various transplant sites and modes of islet delivery to optimize engraftment, short- and long-term survival, and endocrine function.

  • Evaluation of specific treatment regimens including the number of cells required for initial transplantation, maintenance and retreatment regimens, as well as pre-treatment strategies.

  • Immunological mechanisms of early cell destruction and therapeutic interventions to prevent such destruction.

  • Approaches to improve short- and long-term survival by combining islet transplantation with promising tolerogenic molecules and reagents.

  • The role of disease recurrence (i.e., autoimmune injury) in the destruction of transplanted islets.

  • The development of "super" islets, including genetically engineered beta cells and tissues, to improve engraftment and function and to escape autoimmune injury and transplant rejection.

Islet Transplantation: Specific Initiatives

  • Research in non-human primate models.

  • Establishment of a Cooperative Clinical Trial Network for Human Islet Transplantation.

  • Developmental/exploratory research projects and Small Business Innovative Research (SBIR) grants.

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.

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NIAID Archive

Important note: Information in this report was accurate at the time of publication. The state of the science may have evolved since the publication date. Formatting and links on this page are no longer being updated.

Last Updated September 28, 2010

Last Reviewed September 16, 2010