Report of the NIAID Expert Panel on Immune Tolerance

National Institute of Allergy and Infectious Diseases
National Institutes of Health

Introduction

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.

Overall Scientific Approach

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:

• Establishing new, and using existing, clinical research infrastructures to accelerate multi-center studies, including cooperative clinical trial groups in kidney transplantation, islet transplantation, autoimmune and allergic diseases.
• Incorporating studies of underlying mechanisms of the induction, maintenance and loss of tolerance in clinical and non-human primate research.
• Identifying and validating surrogate markers of immune tolerance as well as disease stage, activity and therapeutic response.
• Engaging the participation of private industry by creating an infrastructure that will accelerate quality pre-clinical and clinical research.
• Supporting basic research to expand knowledge of the molecular basis for tolerance induction and maintenance and innovative research to expand the universe of tolerogenic approaches.
• Ensuring the availability of critical research resources, including training programs.

Issues and Questions Addressed by the NIAID Expert Panel

The Expert Panel addressed the following broad issues and questions:

• Within the current context of research on immune-mediated diseases, does the plan address important needs and take advantage of available opportunities?
• What are the major priorities for research on immune tolerance in the short- and the long-term and are these priorities adequately addressed in the plan?
• Does the plan realistically reflect the spectrum of research that may be required?
• What are the most effective ways for the NIAID to maximize collaborations between basic immunologists and clinical researchers to accelerate the development of new knowledge and its application in the clinical setting?
• How can the NIAID foster collaborations with industry and other public/private sector organizations to accelerate research in this area?
• Does the plan offer opportunities to make a contribution toward other important areas of research on immunologic and non-immunologic diseases?

Recommendations

• The panel enthusiastically endorsed the overall scope and timeliness of the research plan, emphasizing the importance of capitalizing rapidly on scientific opportunities to advance the field, particularly for translational and clinical research. The panel also endorsed the overall scientific framework, the key components of the plan, and the major scientific approaches to tolerance induction, stressing the value of focusing on conceptual themes rather than individual agents.
• The panel strongly supported a concerted effort to move the field forward and stressed the importance of a major leadership role for the NIAID in coordinating, directing and managing a broad-based research program and developing collaborations and partnerships between academia, industry and other NIH Institutes. Panel members affirmed that a focused set of research initiatives, including development of supporting infrastructure, would contribute significantly to enhancing understanding of the basic mechanisms of immune tolerance and to the application of new tolerogenic strategies in the clinical setting.
• The panel recommended that the research plan not be limited to a specific timeline. Rather, the plan should be sufficiently flexible to capitalize on the most promising opportunities in a timely fashion.
• The panel acknowledged the limited collaboration between basic and clinical researchers in studies of many immune-mediated diseases. Panel members agreed on the need to create research programs that bring together experts in the relevant basic and clinical disciplines and acknowledged that the expertise necessary to accelerate research frequently cannot be accommodated within a single institution. Therefore, the panel recommended that NIAID provide leadership in fostering a new paradigm designed around an interactive, multi-institutional team approach.
• The panel strongly endorsed NIAID's intent to include studies of underlying mechanisms in conjunction with clinical trials. The panel also strongly endorsed NIAID's plan to establish human immunology cooperative study groups to provide a central resource for the development of standardized assays and the identification and validation of markers.
• The panel endorsed NIAID's plan to support multidisciplinary basic research projects aimed at elucidating the molecular basis of tolerance induction in animal and human systems. This area of investigation will be critical for the future discovery of new approaches. The panel also endorsed the Institute's plan for establishing an innovative research grant program for short-term investigations of truly novel areas.
• The discussion acknowledged the difficulties involved in funding research within a timeframe that is compatible with the needs of industry. The new NIAID accelerated review and award initiative is one approach to ensure that studies of underlying mechanisms can be incorporated into clinical trials in a timely fashion. The plan to establish cooperative clinical trial groups for multiple diseases will provide an infrastructure to rapidly test tolerogenic approaches as they become available. Furthermore, the availability of a centralized resource to conduct studies of underlying mechanisms and develop standardized assays will facilitate collaborations with the pharmaceutical and biotechnology industry. The panel also acknowledged the important role NIH has played in facilitating interactions with the U.S. Food and Drug Administration and expediting many aspects of the regulatory process. The panel strongly supported a leadership role for the NIAID in facilitating NIH-industry-academia collaborations.
• The panel recommended the formation of an advisory group to meet annually and provide advice on the overall direction and progress for all research programs focusing on immune tolerance. Furthermore, it was recommended that this advisory group include a member of the Allergy, Immunology and Transplantation Subcommittee of the National Advisory Allergy and Infectious Diseases Council.
• The panel recommended including in the research plan a component addressing training needs for physicians and Ph.D.s., with a particular emphasis on establishing viable career paths for scientists engaged in translational research and in studies of underlying mechanisms. The new clinical training programs established by the NIH Director are designed to provide career development support which may address some of these very needs. In addition, the panel recommended that NIAID explore additional approaches to build support for career development into some of the research programs outlined in the plan.

The Expert Panel made the following specific recommendations concerning some of the key components of the research plan:

Transplantation

• Non-human primate studies and clinical trials in both kidney and islet transplantation should be pursued rapidly. Initial research efforts should focus on the most promising tolerogenic approaches. However, NIAID should remain flexible so that changes in direction can be accommodated as new information and agents become available.
• Islet transplantation is an exceptional clinical setting to test tolerance induction protocols for several reasons. First, transplant failure is not life threatening and patients can be returned to insulin therapy without long-term deleterious consequences. Second, current efforts in islet transplantation in conjunction with aggressive immunosuppressive therapy have been largely unsuccessful. Furthermore, islet transplantation will provide valuable new information on the ability to induce tolerance in the context of an underlying autoimmune disease.
• NIAID should collaborate with the Juvenile Diabetes Foundation International and the Centers for Disease Control and Prevention in their efforts to establish core facilities for the production and distribution of islets for research purposes.
• Clinical trials in kidney transplantation will also be important given the consistently poor long-term graft survival rates and the potential differences in the ability to induce tolerance to solid organ as compared with cellular transplants.
• Additional strategies should be incorporated into the research plan, including the use of stem cells to deliver the tolerogenic signals and gene transfer approaches for the delivery of immunomodulatory agents.
• NIAID should develop a prospective kidney transplant registry for recipient and donor samples and a stable infrastructure for the conduct of relevant studies. In contrast, a retrospective registry of long-term kidney transplant survivors could be undertaken by the Task Force on Transplant Tolerance, sponsored jointly by the American Society of Transplant Physicians and the American Society of Transplant Surgeons.
• The panel members acknowledged the potential importance of xenotransplantation as one solution to the shortage of donor organs and expressed interest in incorporating this new area of research into the plan. Some members viewed opportunities for human cross-species transplantation as fairly remote. Others highlighted islet transplantation as a setting in which xenotransplantation could make a significant difference. Panel members generally agreed that it will be important to develop methods for, and understand mechanisms of, tolerance induction in the setting of xenotransplantation, as the approaches that are ultimately successful in human allotransplantation are not likely to be directly applicable to organs, cells or tissues from non-human species.

Autoimmune Diseases

• Research in this area should incorporate additional approaches, e.g., the use of anti-cytokine monoclonal antibodies and stem cell and bone marrow transplantation, as well as gene transfer-based therapies for cytokine modulation.
• The panel highlighted a need to develop non-human primate models of autoimmune diseases for evaluating the safety and efficacy of various tolerance induction regimens and agents.
• The panel strongly supported promoting basic research in human immunology, as well as the development of reliable surrogate markers of disease progression and therapeutic response.

Asthma and Allergic Diseases

• The panel stressed that asthma and allergic diseases provide unique opportunities to develop and test approaches aimed at inducing tolerance. Although these diseases are usually not life-threatening, their increasing prevalence, high economic and social costs, and the limitations of current therapies are compelling reasons to explore approaches aimed at the induction of long-term immune tolerance. While much remains to be learned, much is already known about the natural history of allergic diseases, familial predisposition to atopy, and immunologic markers of disease progression. Furthermore, many of the relevant allergens have been identified and have been administered safely in man (albeit, without co-administration of tolerizing agents). Thus, it may be possible to intervene early in at-risk individuals, and the failure to achieve immune tolerance or the need to withdraw investigational therapies would not present the same ethical issues that are anticipated in transplantation and autoimmunity trials.
• The panel strongly recommended that NIAID expand this aspect of the plan and begin clinical trials as early as possible. Panel members also noted that industry is further along than the public sector in supporting clinical studies, including studies of immune deviation, for asthma and allergic diseases. Therefore, the NIAID was encouraged to initiate collaborations with pharmaceutical and biotechnology companies for the joint sponsorship of clinical trials.
• The panel also emphasized gaps in fundamental knowledge relevant to asthma and allergic diseases, noted NIAID's leadership in supporting immunologic studies of asthma, and stressed the importance of increasing NIAID's investment in these areas.

Research Resources

• NIAID can play a critical role in providing the resources necessary to accelerate research on immune tolerance. The panel strongly supported the Institute's plan in this area, including: the development of more clinically relevant animal models; the breeding and maintenance of non-human primates; and the production and distribution of tolerogenic molecules and reagents for basic, pre-clinical and clinical investigations.

NIAID Expert Panel on Immune Tolerance

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