Full Text PA-97-081 BASIC AND CLINICAL RESEARCH ON IMMUNE TOLERANCE NIH GUIDE, Volume 26, Number 24, July 25, 1997 PA NUMBER: PA-97-081 P.T. 34 Keywords: Immunology Clinical Medicine, General Vaccine National Institutes of Health PURPOSE The National Institutes of Health (NIH) invites applications that will elucidate basic mechanisms responsible for inducing and maintaining antigen-specific immune tolerance, that will facilitate translation of experimental knowledge on immune tolerance into clinical therapies for the treatment or prevention of immune-mediated disease, or that will promote more effective development of vaccines by preventing pathogen-induced immune tolerance. HEALTHY PEOPLE 2000 Each NIH PA addresses one or more of 22 Health Promotion and Disease Prevention priority areas identified. These areas can be found via the WWW at URL: http://www.crisny.org/health/us/health7.html ELIGIBILITY Applications may be submitted by for profit and non-profit organizations, public and private, such as universities, colleges, hospitals, laboratories, units of State and local governments, and eligible agencies of the Federal government. Domestic and foreign institutions are eligible to apply for R01 grants. Foreign institutions are not eligible for First Independent Research Support and Transition(FIRST)awards(R29). Racial/ethnic minority individuals, women, and persons with disabilities are encouraged to apply as Principal Investigators. MECHANISMS OF SUPPORT Traditional research project grant (R01)and FIRST(R29) applications may be submitted in response to this announcement. Applications for R01 grants may request up to five (5) years of support; applications for R29 grants must request five years of support. Responsibility for the planning, direction, and execution of the proposed research for all applicable mechanisms of support will be solely that of the applicant. RESEARCH OBJECTIVES Background The immune system is uniquely characterized by its highly diverse and clonally expressed repertoire of lymphocyte receptors that can recognize a very broad spectrum of both foreign and self antigens. Those cells with receptors for self antigens are eliminated, or tolerized, in healthy individuals by a variety of active mechanisms to prevent pathogenic autoimmunity. Autoreactive cells may be physically deleted by the induction of apoptosis after self-antigen recognition, may become anergic without deletion, or may be functionally inhibited by regulatory cytokines or cells. These same mechanisms operate during the induction of tolerance to foreign antigens and may be exploited to inactivate specific, detrimental immune responses without compromising the ability to respond to the remaining universe of pathogens, because tolerance is induced only in those lymphocytes that recognize the offending antigens. Although much has been learned in recent years about the molecular events that distinguish tolerogenic from immunogenic signals, it is still difficult to predict the outcome of antigenic exposure in vivo, and further elucidation of tolerance mechanisms is needed at the basic level. It is important to define the molecular mechanisms that determine whether antigen recognition results in anergy or apoptosis rather than effector or memory cell generation, and to identify genetic factors that regulate these mechanisms. Basic studies on the influence of cytokines on tolerance induction and maintenance, and on the importance of antigen dose, affinity and site of entry are also needed. Immune tolerance is highly relevant to a wide range of clinically important applications. Antigen-specific tolerance induction is a major goal for the treatment or prevention of autoimmune disease and graft rejection, which are currently controlled by nonspecific, immunosuppressive therapies that result in increased rates of infections, cancers and drug-related pathology. Other applications include allergies and asthma, bone marrow replacement and future gene therapy for a large number of human diseases. A greater understanding of tolerogenic processes is also needed to enhance vaccine development, in order to prevent pathogen-induced tolerance during immunization. Very productive basic research in immunology and other fields of study has provided unprecedented opportunities for clinical breakthroughs in this area, due to identification of relevant molecular pathways, new technologies, new reagents and animal model development for in vivo studies. Although work is still needed at the basic level to obtain a more detailed understanding of tolerance vs immunity, the application of existing knowledge to clinical situations has already begun, and an expanded investment in pre- clinical and clinical research is clearly warranted. At present, many clinical studies are conducted by industry to determine efficacy with little emphasis on defining the mechanisms involved. However, enhanced understanding of the mechanisms of immune response vs tolerance in the clinical setting should allow more appropriate selection of therapeutic agents as well as improved results and more predictable outcomes. Research Objectives and Scope Multidisciplinary research focused on the understanding and/or modulation of antigen-specific immune tolerance mechanisms is sought. Both basic and clinical research projects are encouraged, but clinical trials will not be supported on this PA. Specific examples of research areas of interest include, but are not limited to: o Specific immune tolerance mechanisms in human lymphocytes, and novel experimental approaches to define such mechanisms; o Development and validation of clinically relevant animal models of immune tolerance, including transplantation, autoimmune or infectious pathogen systems, in order to define mechanisms of tolerance induction and maintenance, degree of efficacy and potential adverse effects; o Animal models to study tolerance to transplanted allogeneic or xenogeneic lymphoid tissues for application to immune replacement in HIV disease; o Analysis of the genes and biochemical pathways involved in the induction and long-term maintenance of immune tolerance, and molecular pathways by which tolerance is prevented or reversed; o Loss of self-tolerance due to antigen crossreaction during infection or vaccination; o Induction of tolerance by microbial products such as antagonistic peptides or superantigens, or by pathogen-induced, host-derived immunosuppressive factors; o Development of technologies to study tolerance vs immunity at the single cell level to identify mechanisms or immune markers in vivo; o Tolerance induction at mucosal surfaces and the prevention of tolerance to oral vaccines; o Tolerogenic approaches for the primary prevention of asthma and the treatment of allergies; o Definition of tolerance mechanisms in immune-privileged sites, such as the central nervous system, the eye and the maternal-fetal interface; o Analysis of tolerance induction in neonates and in aged individuals; o Effects of chronic maternal infections on immune responses in their progeny; and o Protocols to induce vector-specific tolerance prior to vector- mediated vaccine delivery or gene therapy. INCLUSION OF WOMEN AND MINORITIES IN RESEARCH INVOLVING HUMAN SUBJECTS See NIH Guide of March 18, 1994 for requirements for inclusion of Women and Minorities in research. It is available via the WWW at URL: http://www.nih.gov/grants (select NIH Guide for Grants and Contracts). APPLICATION PROCEDURES Applications are to be submitted on the grant application form PHS 398 (rev. 5/95) and will be accepted on the standard application deadlines as indicated on the application kit. Application kits are available at most institutional offices of sponsored research and may be obtained from the Office of Extramural Outreach and Information, National Institutes of Health, 6701 Rockledge Drive, MSC 7910, Bethesda, MD 20892-7910, telephone (301) 710-0267, email: asknih@odrockm1.od.nih.gov. For purposes of identification and processing, item 2 on the face page of the application must be marked "YES". The PA number and the PA title, "BASIC AND CLINICAL RESEARCH ON IMMUNE TOLERANCE," must also be typed in section 2. The completed, signed original and five legible, single-sided copies of the application must be sent or delivered to: DIVISION OF RESEARCH GRANTS NATIONAL INSTITUTES OF HEALTH 6701 ROCKLEDGE DRIVE, ROOM 1040, MSC 7710 BETHESDA, MD 20892-7710 BETHESDA, MD 20817-7710 (for express/courier service) R29 applications must include at least three (3) sealed letters of reference attached to the face page of the original application. FIRST applications submitted without the required number of reference letters will be considered incomplete and will be returned without review. Applicants from institutions that have a General Clinical Research Center (GCRC) funded by the NIH National Center for Research Resources may wish to identify the Center as a resource for conducting the proposed research. If so, a letter of agreement from the GCRC Program Director must be included in the application material. REVIEW CONSIDERATIONS Review Procedures Applications will be assigned on the basis of established PHS referral guidelines. Upon receipt, applications will be reviewed for completeness by the NIH Division of Research Grants. Incomplete applications will be returned to the applicant without further consideration. Applications will be reviewed for scientific and technical merit by study sections of the Division of Research Grants, NIH, in accordance with the standard NIH peer review procedures. As part of the initial merit review, all applications will receive a written critique and undergo a process in which only those applications deemed to have the highest scientific merit, generally the top half of the applications under review, will be discussed, assigned a priority score, and receive a second level review by the appropriate national advisory council. Review Criteria The five criteria to be used in the evaluation of grant applications are listed below. The goals of NIH-supported research are to advance our understanding of biological systems, improve the control of disease, and enhance health. The reviewers will comment on the following aspects of the application in their written critiques in order to judge the likelihood that the proposed research will have a substantial impact on the pursuit of these goals. Each of these criteria will be addressed and considered by the reviewers in assigning the overall score weighting them as appropriate for each application. Note that the application does not need to be strong in all categories to be judged likely to have a major scientific impact and thus deserve a high priority score. For example, an investigator may propose to carry out important work that by its nature is not innovative but is essential to move a field forward. 1. Significance. Does this study address an important problem? If the aims of the application are achieved, how will scientific knowledge be advanced? What will be the effect of these studies on the concepts or methods that drive this field? 2. Approach. Are the conceptual framework, design, methods, and analyses adequately developed, well-integrated, and appropriate to the aims of the project? Does the applicant acknowledge potential problem areas and consider alternative tactics? 3. Innovation. Does the project employ novel concepts, approaches or method? Are the aims original and innovative? Does the project challenge existing paradigms or develop new methodologies or technologies? 4. Investigator. Is the investigator appropriately trained and well suited to carry out this work? Is the work proposed appropriate to the experience level of the principal investigator and other researchers (if any)? 5. Environment. Does the scientific environment in which the work will be done contribute to the probability of success? Do the proposed experiments take advantage of unique features of the scientific environment or employ useful collaborative arrangements? Is there evidence of institutional support? The initial review group will also examine: the appropriateness of proposed project budget and duration; the adequacy of plans to include both genders and minorities and their subgroups as appropriate for the scientific goals of the research and plans for the recruitment and retention of subjects; the provisions for the protection of human and animal subjects; and the safety of the research environment. AWARD CRITERIA Applications will compete for available funds with all other favorably recommended applications. The following will be considered when making funding decisions: quality of the proposed project as determined by peer review, program balance, and availability of funds. INQUIRIES Each sponsoring Institute/Center is identified below. A staff contact for electronic and telephone is listed and inquiries regarding programmatic (research scope, eligibility and responsiveness) issues are encouraged. The opportunity to clarify any issues or answer questions from potential applicants is welcome. National Institute of Allergy and Infectious Diseases Division of Allergy, Immunology, and Transplantation Helen Quill, Ph.D. Telephone: (301) 496-7551 Fax: (301) 402-2571 EMAIL: hq1t@nih.gov National Institute of Allergy and Infectious Diseases Division of Microbiology and Infectious Diseases Lee Hall, M.D., Ph.D. Telephone: (301) 496-2544 Fax: (301) 402-2508 EMAIL: lh24g@nih.gov National Institute of Allergy and Infectious Diseases Division of Acquired Immunodeficiency Syndrome Scott Cairns, Ph.D. Telephone: (301) 496-8197 Fax: (301) 402-3211 EMAIL: sc160p@nih.gov National Heart, Lung and Blood Institute Judith Massicot-Fisher, Ph.D. Telephone: (301) 435-0504 Fax: (301) 480-1454 EMAIL: jm294z@nih.gov National Institute on Aging Dr. Anna M. McCormick Telephone: (301) 496-6402 Fax: (301) 402-0010 EMAIL: am38k@nih.gov National Institute of Child Health and Human Development Allan Lock, D.V.M. Telephone: (301) 496-5541 Fax: (301) 402-4083 EMAIL: locka@hd01.nichd.nih.gov AUTHORITY AND REGULATIONS Research under this announcement will be supported under programs cited in the Catalog of Federal Assistance (CFDA). The PHS portion of the CFDA is available at URL: http://odphp.osophs.dhhs.gov/cfda/index.htm. Awards will be administered under PHS grants policies and Federal Regulations 42 CFR Part 52 and 45 CFR Part 74. This program is not subject to the intergovernmental review requirements of Executive Order 12372 or Health Systems Agency review. The Public Health Service strongly encourages all grant recipients to provide a smoke-free workplace and promote the non-use of all tobacco products. This is consistent with the PHS mission to protect and advance the physical and mental health of the American people. .
Return to NIH Guide Main Index
Office of Extramural Research (OER) |
National Institutes of Health (NIH) 9000 Rockville Pike Bethesda, Maryland 20892 |
Department of Health and Human Services (HHS) |
||||||||
Note: For help accessing PDF, RTF, MS Word, Excel, PowerPoint, Audio or Video files, see Help Downloading Files. |