Full Text AI-96-003 TRANSPLANTATION TOLERANCE NIH GUIDE, Volume 25, Number 14, May 3, 1996 RFA: AI-96-003 P.T. 34 Keywords: Transplantation of Organs Immunology National Institute of Allergy and Infectious Diseases Juvenile Diabetes Foundation, International Letter of Intent Receipt Date: August 10, 1996 Application Receipt Date: October 8, 1996 APPLICATIONS IN RESPONSE TO THIS REQUEST FOR APPLICATIONS (RFA) MUST BE PREPARED USING A MODIFIED (ABBREVIATED) GRANT APPLICATION FORMAT; SPECIFIC INSTRUCTIONS FOR COMPLETING THE APPLICATION ARE IN AN NIAID BROCHURE ENTITLED "INSTRUCTIONS FOR ABBREVIATED APPLICATIONS FOR MULTI-PROJECT AWARDS" (February 1996). PURPOSE The National Institute of Allergy and Infectious Diseases (NIAID) of the National Institutes of Health (NIH) and the Juvenile Diabetes Foundation, International (JDFI) invite applications for basic, pre- clinical and clinical studies to determine the mechanisms of immunologic tolerance that will enhance solid organ and tissue graft survival. This Request for Applications (RFA) for Program Project Grants is intended to stimulate collaboration between clinicians and basic immunologists to identify and characterize the immune mechanisms responsible for enhancing graft survival by inducing tolerance to the donor organ or tissue. The investigation of tolerance induction for the prevention or treatment of autoimmune disease could advance understanding of tolerance induction in the transplant setting. Thus, applications incorporating investigations of tolerance induction for autoimmune disease in the transplant setting are encouraged. Applications should be submitted to and will be reviewed according to usual NIH peer review procedures. Funds for each Program Project to be awarded under this RFA will be provided by the NIAID and the JDFI. To have an application reviewed and considered for funding, applicants must authorize the NIAID, in writing, to provide to the JDFI a copy of their letter of intent, application and NIH prepared summary statement of the initial review HEALTHY PEOPLE 2000 The Public Health Service (PHS) is committed to achieving the health promotion and disease prevention objectives of "Healthy People 2000," a PHS-led national activity for setting priority areas. This RFA, Transplantation Tolerance, is related to the priority area of diabetes and chronic disabling diseases. Potential applicants may obtain a copy of "Healthy People 2000" (Full Report: Stock No. 017-001-00474-0 or Summary Report: Stock No. 017-001-00473-1) through the Superintendent of Documents, Government Printing Office, Washington, DC 20402-0325 (telephone 202-512-1800). ELIGIBILITY REQUIREMENTS Research grant applications may be submitted by domestic for-profit and non-profit organizations, public and private institutions, such as universities, colleges, hospitals, laboratories, units of State and local governments, and eligible agencies of the Federal government. Foreign organizations are not eligible to apply to the NIH. However, the JDFI will separately consider non-U.S. applications (contact Sara King of the JDFI at 212-479-7524 for more information). Racial/ethnic minority individuals, women, and persons with disabilities are encouraged to apply as Principal Investigators. MECHANISM OF SUPPORT The mechanism of support will be the program project (P01) grant. This mechanism supports broadly based multi-disciplinary research programs that have a well-defined central research focus, theme, or objective. An important feature of the program project is that the interrelationships of the individual scientifically meritorious projects will result in a greater contribution to the overall program goals than if each project were pursued individually. The program project grant consists of a minimum of three interrelated individual research projects that contribute to the program objective. The program project grant also can provide support for certain common resources termed cores. Such resources should be utilized by two or more projects within the program project. Responsibility for the planning, direction, and execution of the proposed project will be solely that of the applicant. The total project period may not exceed five years. At this time, the NIAID is administratively limiting the duration of P01 grants to four years; this administrative limitation may change in the future. The earliest anticipated award date is July 1997. FUNDS AVAILABLE The estimated total funds (direct and indirect costs) available for the first year of support for this RFA will be $3.0 million: $2.0 million from NIAID and $1.0 million from JDFI. In fiscal year 1997, the NIAID and the JDFI anticipate jointly funding approximately four to five program projects related to this RFA. Approximately 65 percent of the total costs of each grant will be funded by the NIAID and approximately 35 percent by the JDFI. This level of support is dependent on the receipt of a sufficient number of applications of high scientific merit. Applications may not request budgets in excess of $750,000 Total Costs (direct and indirect) in the first year. NIH is currently limiting annual inflationary increases to no more than four percent for future years. Funding rules and policies, including the determination of allowable indirect costs, of each funding organization will be applicable. Post award administration will conform to current policies and requirements that govern the research grant programs of the NIH and the JDFI as appropriate. Although this program is provided for in the financial plans of the NIAID and the JDFI, awards pursuant to this RFA are contingent upon the availability of funds for this purpose. Funding beyond the first and subsequent years of the grant will be contingent upon satisfactory progress during the preceding years and availability of funds. At this time, it has not determined whether or how this solicitation will be continued beyond the present RFA. Administrative adjustments in the project period and/or amount of support may be required at the time of award. RESEARCH OBJECTIVES Background In 1994, more than 19,000 solid organ transplants were performed in the United States. Advances in surgical methods and current immunosuppressive therapies have improved short-term survival; however, long-term survival rates remain poor. For example, kidney transplantation has a one-year graft survival rate of 85 to 95 percent; however, the survival rate at five years is about 50 percent. These short graft survival rates demonstrate the inadequacy of the current clinical regimens to ensure long-term graft survival. In addition, if organ failure is due to an autoimmune disease, survival rates are significantly decreased. For example, diabetes, which can cause end-stage diabetic nephropathy or systemic lupus erythematosus, which can result in glomerulonephritis, can lead to significantly decreased kidney graft survival rates at five years post transplant. The ability to induce donor-specific tolerance could significantly improve long-term graft survival, reduce or eliminate the continuing need for expensive, toxic and non-specific immunosuppressive therapy and enhance the quality of life. Recent investigations have provided insights into how transplant tolerance may be accomplished. Studies have demonstrated that "passenger lymphocytes" carried within a transplanted organ may affect graft survival. This is particularly noticeable in liver transplantation. The liver, which contains a very large number of lymphoid cells, does not induce an immune response leading to rejection. Instead, it appears to induce tolerance. One possible mechanism leading to this tolerance may be that the donor lymphoid cells emigrate from the liver and take up residence in the recipient's immune organs, such as the lymph nodes. This cohabitation of large numbers of donor lymphocytes with recipient immune cells might "re-educate" the recipient immune system so that the donor organ is not recognized as foreign. In an attempt to mimic this process, transfusions of donor blood or bone marrow have been used to enhance solid organ graft survival in animal models and in clinical trials. These studies and trials have not yet provided definitive results and the mechanisms whereby the introduction of donor cells might lead to tolerance are still not understood. Therefore, further pre-clinical studies are needed to help establish the basis for clinical use of tolerance induction. Basic research has shed light on some of the mechanisms involved in tolerance induction. An example is how co-stimulation can be modulated to affect T-cell responses. Blockade of this "second signal" during delivery of the antigen specific T-cell receptor mediated "first signal" can result in antigen specific tolerance in some animal transplant models. In addition, experiments examining the role of cytokines in modulating the immune response have shown that the balance of cytokines can direct the immune response to either the TH1 type of inflammatory response and graft rejection, or to the TH2 type of suppressor/regulator response that might lead to improved graft survival. Although considerable progress has been made in the past few years, it is clear that a better understanding of how to manipulate the immune response to allow routine donor-specific tolerance induction is required. While these examples are illustrative of advances that have been made already, the purpose of this RFA is to extend and expand research to further the understanding of the processes and mechanisms leading to transplant tolerance. Research Objectives and Scope The objectives of this RFA are to identify and characterize the cellular and molecular mechanisms responsible for donor-specific tolerance and to identify and examine approaches for modulating the immune response to tolerize the transplant recipient. The scope of research to be supported under this RFA includes, but are is not limited to, the following broad areas of interest and examples of possible specific investigations. The examples are not meant to be directive, but illustrative of areas that remain to be investigated further. Investigators are encouraged to develop novel approaches to understanding the mechanisms responsible for the induction and maintenance of donor-specific tolerance. o EVALUATIONS OF THE IMMUNE RESPONSE TO ORGAN ALLOGRAFTS AND DEVELOPMENT OF WAYS TO MANIPULATE THE RESPONSE Studies to determine the mechanism of action of HLA- derived peptides and test the utility of these peptides in animal models and transplant recipients. The identification, assessment and investigation of the mechanisms of therapies that modulate underlying autoimmune diseases, such as insulin dependent diabetes mellitus (IDDM), to prevent damage to a transplanted organ. o ELUCIDATION OF THE IMPORTANT CELLULAR AND MOLECULAR EVENTS OF BOTH THE INDUCTION AND EFFECTOR PHASES OF THE IMMUNE RESPONSE Investigations to determine the indicators of immune reactions that are predictive of post-transplant graft survival and to develop clinically useful post-transplant monitoring protocols capable of predicting durable transplant tolerance. Studies to determine the relative roles and mechanisms involved of indirect vs. direct antigen presentation in the ability to induce transplant tolerance and to design approaches to manipulate the system to favor tolerance vs. destructive immune response. Definition and characterization of the role of Major and Minor Histocompatibility Antigens in both acute and chronic graft rejection and development of regimens to ensure tolerance to these antigens to promote long-term graft survival. o INVESTIGATIONS OF APPROACHES TO THE DEVELOPMENT OF THERAPEUTIC STRATEGIES TO IMPROVE LONG-TERM GRAFT SURVIVAL. Evaluations of the efficacy and mechanisms of action of multiple agent interventional therapies in vivo in animal models of tolerance induction in the presence or absence of current immunosuppressive drug regimens. Studies to delineate the mechanisms of action of immunomodulatory molecules in transplant rejection and tolerance using appropriate animal models, e.g., manipulating the immune system to affect the balance of inflammatory vs. suppressive reactions by the use of cytokines, receptors, competitors, inhibitors and mimicry molecules delivered in vivo. Development of approaches to promote transplant tolerance by treating either the donor organs or recipients using gene therapy. Proposed projects and the knowledge generated by this research must be applicable to human disease and human transplantation. Studies of human transplantation in the setting of autoimmune diseases, such as IDDM, are particularly sought. While animal models may be proposed, any such model must be an acceptable approximation of the human condition. In addition, any proposed animal or human studies must demonstrate the efficacy of the treatment under conditions of generally accepted standard immunosuppressive therapy in humans. Therefore, although studies focusing exclusively on infusion of donor immune system cells will be considered, this type of study must be focused on understanding the basic mechanisms of transplant tolerance induction and maintenance. SPECIAL REQUIREMENT The NIAID and the JDFI plan to sponsor an annual meeting to encourage the exchange of information among investigators supported under this RFA, as well as to foster collaborative efforts and identify resources that would enhance the productivity of this research program. Applications should include a statement indicating the willingness of the applicant institution to participate in such annual meetings. For this purpose, travel funds for an annual two-day meeting, to be held in the Washington, DC area, should be included in the budget request. INCLUSION OF WOMEN AND MINORITIES IN RESEARCH INVOLVING HUMAN SUBJECTS It is the policy of the NIH that women and members of minority groups and their sub-populations must be included in all NIH supported biomedical and behavioral research projects involving human subjects, unless a clear and compelling rationale and justification is provided that inclusion is inappropriate with respect to the health of the subjects or the purpose of the research. This new policy results from the NIH Revitalization Act of 1993 (Section 492B of Public Law 103-43) and supersedes and strengthens the previous policies (Concerning the Inclusion of Women in Study Populations, and Concerning the Inclusion of Minorities in Study Populations), which have been in effect since 1990. The new policy contains some provisions that are substantially different from the 1990 policies. All investigators proposing research involving human subjects should read the "NIH Guidelines For Inclusion of Women and Minorities as Subjects in Clinical Research," which have been published in the Federal Register of March 28, 1994 (FR 59 14508-14513) and printed in the NIH Guide for Grants and Contracts, Volume 23, Number 11, March 18, 1994. Investigators also may obtain copies of the policy from the program staff listed under INQUIRIES. Program staff may also provide additional relevant information concerning the policy. LETTER OF AUTHORIZATION Applicants must submit a brief letter to the NIAID, co-signed by the Principal Investigator and the official signing for the applicant institution, indicating that they will allow their applications to be considered for funding by the JDFI. This letter may be combined with the Letter of Intent or may be submitted directly to Dr. Stephen Rose at the address shown in "INQUIRIES" below. If a Letter of Authorization is not submitted and signed by the appropriate institutional officials, the application will be considered incomplete and will be returned to the applicant without review. All materials relating to the application will be promptly forwarded to the JDFI by the NIAID. The summary statements for such applications will be shared with the JDFI at the time of their availability. LETTER OF INTENT Prospective applicants are asked to submit, by August 10, 1996, a letter of intent that includes a descriptive title of the overall proposed research, the name, address, and telephone number of the Principal Investigator, a list of the key investigators and their institution(s), and the number and title of this RFA. Although the letter of intent is not required, is not binding, does not commit the sender to submit an application, and does not enter into the review of subsequent applications, the information that it contains allows NIAID staff to estimate the potential review workload and to avoid conflict of interest in the review. The letter of intent is to be sent to Dr. Stephen Rose, Ph.D. at the address listed under INQUIRIES. APPLICATION PROCEDURES APPLICATIONS IN RESPONSE TO THIS REQUEST FOR APPLICATIONS (RFA) MUST BE PREPARED USING A MODIFIED (ABBREVIATED) GRANT APPLICATION FORMAT; SPECIFIC INSTRUCTIONS FOR COMPLETING THE APPLICATION ARE IN AN NIAID BROCHURE ENTITLED "INSTRUCTIONS FOR ABBREVIATED APPLICATIONS FOR MULTI-PROJECT AWARDS" (February 1996). Applications are to be submitted on the standard research grant application form PHS 398 (rev. 5/95). Applications kits are available at most institutional offices of sponsored research and may be obtained from the Grants Information Office, Office of Extramural Outreach and Information Resources, 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" and the RFA number "AI-96-003" and the words "Transplantation Tolerance" must be typed in. Applications must be received by October 8, 1996. Applications that are not received as a single package on the receipt date or that do not conform to the instructions contained in PHS 398 (rev. 5/95) Application Kit (as modified in, and superseded by, the NIAID BROCHURE ENTITLED "INSTRUCTIONS FOR ABBREVIATED APPLICATIONS FOR MULTI-PROJECT AWARDS"), will be judged non-responsive and will be returned to the applicant. The RFA label available in the application form PHS 398 must be affixed to the bottom of the face page. Failure to use this label could result in delayed processing of the application such that it may not reach the review committee in time for 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 GCRC as a resource for conducting the proposed research. If so, a letter of agreement from either the GCRC program director or principal investigator could be included with the application. It is highly recommended that the appropriate NIAID program contact be consulted before submitting the letter of intent (See program contact under INQUIRIES). Submit a signed, typewritten original of the application, including the checklist, and three signed, exact, single-sided photocopies, in one package to: DIVISION OF RESEARCH GRANTS NATIONAL INSTITUTES OF HEALTH 6701 ROCKLEDGE DRIVE, ROOM 1040 - MSC 7710 BETHESDA, MD 20892-7710 BETHESDA, MD 20817 (for express/courier service) At the time of submission, two additional exact copies of the grant application and all five sets of any appendix material must be sent to Dr. Olivia Preble at the address listed under INQUIRIES. Concurrent submission of an R01 and a Component Project of a Multi-project Application: Current NIH policy permits a component research project of a multi-project grant application to be concurrently submitted as a traditional individual research project (R01) application. If, following review, both the multi-project application and the R01 application are found to be in the fundable range, the investigator must relinquish the R01 and will not have the option to withdraw from the multi-project grant. This is an NIH policy intended to preserve the scientific integrity of a multi-project grant, which may be seriously compromised if a strong component project(s) is removed from the program. Investigators wishing to participate in a multi-project grant must be aware of this policy before making a commitment to the Principal Investigator and awarding institution. SPECIAL INSTRUCTIONS FOR COMPLETION OF APPLICATIONS IN RESPONSE TO THIS RFA A status report on NIH reinvention activities was presented in the NIH GUIDE (Vol. 24, No. 40, November 24, 1995. Two of these activities are: (1) the use of "Just-in-Time" grant applications; and (2) modular budget requests and funding. Both "Just-in-Time" and "Modular Budgeting" together with special page limits on the research plan are used for applications for this RFA. JUST-IN-TIME GRANT APPLICATIONS. The basic principle of "Just-in-Time" is to simplify and reduce the administrative and paperwork burdens of preparing an NIH grant application without compromising the initial review group determination of scientific merit or reasonableness of the proposed budget. To that end, both less and less detailed information is required in "Just-in-Time" applications. Applications in response to this RFA are to use the "Just-in-Time" format. MODULAR GRANTS. Applications are submitted and/or awards made with direct costs in modules (multiples) of a given amount ($25,000 for this RFA), with work proposed within these incremental categories. The model involves using pre-established funding levels for awards and acknowledging that grantees can and do rebudget post-award. This process eliminates the need for many budget details, thereby relieving administrative burdens on both NIH staff and grantee organizations and simplifying cost management by NIH program staff. RESEARCH PLAN PAGE LIMIT. Sections A - D of the research plan are limited to 20 pages for: (1) the overview of the proposed program; (2) each research project; and (3) each core. The NIAID brochure, "INSTRUCTIONS FOR ABBREVIATED APPLICATIONS FOR MULTI-PROJECT AWARDS", presents specific instructions for sections of the PHS 398 (rev. 5/95) application form that should be completed differently than usual. Some sections in the application are modified and others should not be completed for submission of the application, but will be requested if the application receives a score in the fundable range. For all other items in the application, follow the usual instructions on pages 5-20 of the PHS 398 booklet. REVIEW CONSIDERATIONS Review Procedures Upon receipt, applications will be reviewed for completeness by the NIH Division of Research Grants (DRG) and for responsiveness by NIAID staff. Incomplete and/or non-responsive applications will be returned to the applicant without further consideration. Applications that are complete and responsive to the RFA will be evaluated for scientific and technical merit by an appropriate peer review group convened by the NIAID in accordance with the review criteria stated below. As part of the initial merit review, a process (triage) may be used by the initial review group in which applications will be determined to be competitive or non-competitive based on their scientific merit relative to other applications received in response to the RFA. Applications judged to be competitive will be discussed and be assigned a priority score. Applications determined to be non-competitive will be withdrawn from further consideration and the Principal Investigator and the official signing for the applicant organization will be notified. The second level of review will be provided by the National Advisory Allergy and Infectious Diseases Council. In addition, the JDFI Lay Review Committee and Board will review all applications. Review Criteria The general criteria for P01 grant applications are presented in the NIAID BROCHURE. Additional review criteria specific to this RFA are: o A well-defined, unifying goal or problem area of research to which each project relates and contributes, thereby producing a research environment that allows each research effort to share the creative strengths of others. o A program director who possesses recognized scientific and administrative competence. He/she must demonstrate a substantial commitment to the program in time and effort, thereby exercising leadership in providing overall direction and in upholding rigorous scientific conduct. o Each research project must, as assessed by peer review, stand on its own independent scientific merit, as well as complement other projects whenever feasible. o The projects require the participation of established investigators in several disciplines or investigators with special expertise in several areas of one discipline. All investigators must contribute to and share the responsibilities of fulfilling the program objective. o In applications studying transplantation in an autoimmune setting, the ability of the proposed research to provide knowledge of basic, molecular and genetic mechanisms in the pathogenesis of the underlying autoimmune disorder and the development of innovative therapies for treating the human autoimmune disease to prevent subsequent graft loss due to the autoimmune disease. The appropriateness of the proposed experimental plan to validate the utility of the chosen strategy will be considered in this regard. AWARD CRITERIA Funding decisions will be made on the basis of scientific and technical merit as determined by peer review, program priorities, and the availability of funds. INQUIRIES Written and telephone inquiries concerning this RFA are encouraged. The opportunity to clarify any issues or questions from potential applicants is welcome. Requests for the NIAID brochure "INSTRUCTIONS FOR ABBREVIATED APPLICATIONS FOR MULTI-PROJECT AWARDS" as well as inquiries regarding programmatic issues, may be directed to: Stephen M. Rose, Ph.D. Division of Allergy, Immunology, and Transplantation National Institute of Allergy and Infectious Disease Solar Building, Room 4A14 6003 Executive Boulevard Bethesda, MD 20892-7640 Rockville, MD 20852 (for express/courier service) Telephone: (301) 496-5598 FAX: (301) 402-2571 Email: sr8j@nih.gov Direct inquiries regarding application preparation and review issues; address the letter of intent, and mail two copies of the application and all five sets of appendices to: Oliva Preble, Ph.D. Division of Extramural Activities National Institute of Allergy and Infectious Diseases Solar Building, Room 4C-19 6003 Executive Boulevard Bethesda, MD 20892-7610 Rockville, MD 20852 (for express/courier service) Telephone: (301) 496-8208 FAX: (301) 402-2638 Email: op2t@NIH.GOV Direct inquiries regarding fiscal matters to: Ms. Victoria Putprush Division of Extramural Activities National Institute of Allergy and Infectious Diseases Solar Building, Room 4C-25 6003 Executive Boulevard Bethesda, MD 20892-7610 Rockville, MD 20852 (for express/courier service) Telephone: (301) 496-7075 FAX: (301) 480-3780 Email: vp8g@NIH.GOV Schedule Letter of Intent Receipt Date: August 10, 1996 Application Receipt Date: October 8, 1996 Scientific Review Date: February 1997 Advisory Council Date: May 1997 Earliest Award Date: July 1997 AUTHORITY AND REGULATIONS This program is supported under authorization of the Public Health Service Act, Sec. 301 (c), Public Law 78-410, as amended. The Catalogue of Federal Domestic Assistance Citation is No. 93.855 - Immunology, Allergy, and Transplantation Research as appropriate. 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 PHS strongly encourages all grant and contract recipients to provide a smoke-free workplace and promote the non-use of all tobacco products. In addition, Public Law 103-227, the Pro-Children Act of 1994, prohibits smoking in certain facilities (or in some cases, any portion of a facility) in which regular or routine education, library, day care, health care or early childhood development services are provided to children. This is consistent with the PHS mission to protect and advance the physical and mental health of the American people. .
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