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NIAID Plan for Research on Immune Tolerance

Part 3: Detailed Research Plan


D: Cross-Cutting Research

Human Immunology Cooperative Study Groups

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:

  • The development of markers for the induction, maintenance and loss of tolerance.

  • Assessment of the mechanisms of action of tolerogenic reagents being tested in pre-clinical and clinical studies.

  • Studies to define the immunological mechanisms of immune-mediated diseases and the acceptance, survival and rejection of transplanted solid organs and cells.

  • Further development of non-invasive alternatives to surveillance biopsies to assess graft function and predict rejection (e.g., peripheral blood and urine).

  • Development and application of DNA/microarray chip technologies.

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.

Research Resources

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:

  • Establishment of a Good Manufacturing Practice Facility to produce and distribute promising tolerogenic molecules to NIAID-supported investigators for basic, preclinical and clinical studies.

  • Expansion of NIAID's program for the breeding and distribution of transgenic and knock-out mice for studies of immune tolerance.

  • Support for the breeding and maintenance of non-human primates through the Regional Primate Centers of the National Center for Research Resources.

  • Research Training Programs.

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.

Exploratory/Developmental Research Projects

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:

  • Novel targets to divert signal transduction pathways.

  • Cell or tissue engineering to induce tolerance versus immunity.

  • Innovative technical approaches to monitor tolerance induction and maintenance in vivo.

  • Novel diagnostic techniques for more rigorous classification of immune-mediated diseases.

  • New animal models of immune-mediated human disease.

Basic Studies for Future Discovery

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:

  • Definitive studies on the mechanisms by which currently effective or promising biological and pharmaceutical agents produce tolerance in vitro or in vivo and factors that might limit their usefulness in clinical applications.

  • The identification and characterization of promising new targets of tolerance induction.

  • The basis for differences in tolerance induced by mucosal versus systemic routes.

  • The molecular mechanisms responsible for the loss of tolerance to specific antigens.

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Archive

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 29, 2010

Last Reviewed September 16, 2010