INNOVATIVE GRANTS ON IMMUNE TOLERANCE RELEASE DATE: April 4, 2003 RFA: AI-03-010 (This RFA has been modified, see RFA-AI-05-023) National Institute of Allergy and Infectious Diseases (NIAID) ( National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) ( National Heart, Lung and Blood Institute (NHLBI) ( CATALOGUE OF FEDERAL DOMESTIC ASSISTANCE NUMBERS: No. 93.855, Immunology, Allergy, and Transplantation Research No. 93.856, Microbiology and Infectious Diseases Research No. 93.847, Diabetes, Endocrinology and Metabolism Research No. 93.837, Heart and Vascular Diseases Research No. 93.838, Lung Diseases Research LETTER OF INTENT RECEIPT DATE: June 15, 2003 APPLICATION RECEIPT DATE: July 15, 2003 THIS RFA CONTAINS THE FOLLOWING INFORMATION o Purpose of this RFA o Research Objectives o Mechanism(s) of Support o Funds Available o Eligible Institutions o Individuals Eligible to Become Principal Investigators o Special Requirements o Where to Send Inquiries o Letter of Intent o Submitting an Application o Peer Review Process o Review Criteria o Receipt and Review Schedule o Award Criteria o Required Federal Citations PURPOSE OF THIS RFA The National Institute of Allergy and Infectious Diseases (NIAID), the National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK), and the National Heart, Lung and Blood Institute (NHLBI), National Institutes of Health (NIH), invite applications for exploratory/developmental research project grants to support novel work on the molecular mechanisms and applications of antigen-specific immune tolerance, which is the selective and long-term inactivation of immune responses. The projects should involve a high degree of innovation, and have a clearly articulated potential to improve understanding of immune tolerance. Investigators new to immune tolerance are particularly encouraged to develop projects in this area. Research projects will be supported by the exploratory/developmental research grant mechanism, which provides the resources to carry out preliminary tests of feasibility for new research hypotheses. Clinical trials are excluded from this RFA, as are studies on HIV/AIDS and behavioral research. However, research involving human tissues or samples is encouraged. RESEARCH OBJECTIVES Background We are growing closer to the day when allergies, autoimmune diseases, and transplant rejection will be treated by selective inactivation of harmful immune responses, without the global impairment of protective immunity that is currently imposed by immunosuppressive drugs. The past two decades of immunological research have produced a wealth of information on the cells and molecules involved in immunoregulation, identifying a variety of approaches to be tested for selective immune inactivation. Of particular note is the success achieved in defining certain mechanisms by which antigen-specific immune tolerance can be induced in animal model systems. Some of these mechanisms are now being tested in human autoimmune diseases, allergy, and allotransplantation. It is likely that a variety of protocols will be needed to control the broad range of immune-mediated diseases that exist in humans. Such diseases afflict millions of individuals and often involve serious recurring or long-term chronic illness. Promising opportunities and important challenges exist to develop effective protocols for the antigen-specific prevention, or even reversal, of detrimental immune responses in human allergy, asthma, autoimmune diseases, and transplantation. The application of new technologies such as soluble MHC-peptide reagents, the ability to conduct single cell assays and microarray analyses, and progress in the genetic manipulation of normal cells, offer opportunities for more definitive analyses of the human immune system and for the construction of experimental animal systems that more directly model human diseases, such as autoimmune hepatitis, primary biliary cirrhosis, sclerosing cholangitis, and inflammatory bowel diseases such as celiac disease. Research Objectives and Scope The goal of this initiative is to support truly innovative projects on immune tolerance and to encourage investigators working in other areas of research to bring novel perspectives and expertise to this field. For example, concepts and methodologies from genetics, in vivo imaging, and cell migration and localization research may provide new insights into controlling immune tolerance. High risk, high impact projects are sought that have the potential to significantly increase our understanding of the mechanisms that induce long-lived, antigen-specific immune tolerance for application to human disease. This program will not support clinical trials, behavioral studies, or HIV/AIDS research. Studies on basic principles of immunological tolerance, and immune tolerance as a focus for the prevention/treatment of immune-mediated diseases such as allergy, asthma, transplantation, and autoimmune diseases are of interest to the NIAID. Studies relevant to the etiology and/or treatment of type 1 diabetes are of particular interest to the NIDDK. In addition, the NIDDK is interested in applications that study the etiology or potential therapy of immune-mediated renal diseases, such as renal vasculitis and autoimmune glomerulonephritis. The NHLBI is interested in studies on the development of tolerance specific for heart and lung tissues, and heart and lung transplantation; use of the oral route of antigen administration to induce lung airway tolerance; and the analysis of tolerance in young animals, before the immune system matures. The characterization of specific immunoregulatory cytokines in the setting of chronic inflammation is also of interest to all ICs. Highly innovative, short-term pilot projects to evaluate new, but as yet untested, concepts in immune tolerance may include, but are not limited to, research in the following areas: o the mechanistic basis for differences in tolerance induced by systemic versus mucosal routes; o the identification and characterization of promising new T, B, or antigen- presenting cell molecular targets for tolerance induction, including antigen identification; o the parameters of tolerance induction to non-peptide self antigens, alloantigens, or allergens; o the molecular events responsible for the loss of tolerance to self antigens; o methods to extend the duration of antigen-specific tolerance; o novel technologies to identify and quantitate tolerant T or B cells; o the development or application of cell and tissue engineering methods to predictably induce tolerance rather than immunity; o the characterization of novel, antigen-specific immunosuppressive cell types; o the identification of mechanisms by which currently known tolerogenic biological or pharmaceutical agents induce and/or maintain immune tolerance; o the development of simple and reliable assays for the identification of tolerant states in humans; and o the development of vaccine strategies to induce antigen-specific tolerance to disease-related autoantigens or allergens. MECHANISM OF SUPPORT This RFA will use the NIH Exploratory/Developmental Research Project Grant (R21) award. The total requested project period for an application submitted in response to this RFA may not exceed two years. The applicant will be solely responsible for planning, directing, and executing the proposed project. This RFA is a one-time solicitation. Future unsolicited, competing-continuation applications based on this project will compete with all investigator- initiated applications and will be reviewed according to the customary peer review procedures. The anticipated award date is February, 2004. NIH uses R21 grants to provide short-duration support for preliminary studies of a highly speculative nature, which are expected to yield, within this time frame, sufficient information upon which to base a well-planned and rigorous series of further investigations. This RFA uses just-in-time concepts. It also uses the modular budgeting format. (see Specifically, if the investigator is submitting an application with direct costs in each year of $250,000 or less, use the modular format. This program does not require cost sharing as defined in the current NIH Grants Policy Statement at FUNDS AVAILABLE The participating IC(s) intends to commit approximately $5,400,000 in FY 2004 to fund 22 to 28 new grants in response to this RFA. An applicant may request a project period of up to two years and a budget for direct costs of up to $150,000 per year. Because the nature and scope of the proposed research will vary from application to application, it is anticipated that the size and duration of each award will also vary. Although the financial plans of the IC(s) provide support for this program, awards pursuant to this RFA are contingent upon the availability of funds and the receipt of a sufficient number of meritorious applications. ELIGIBLE INSTITUTIONS The applicant may submit (an) application(s) if the institution has any of the following characteristics: o For-profit or non-profit organizations o Public or private institutions, such as universities, colleges, hospitals, and laboratories o Units of State and local governments o Eligible agencies of the Federal government o Domestic or foreign o Faith-based or community-based organizations INDIVIDUALS ELIGIBLE TO BECOME PRINCIPAL INVESTIGATORS Any individual with the skills, knowledge, and resources necessary to carry out the proposed research is invited to work with their institution to develop an application for support. Individuals from underrepresented racial and ethnic groups as well as individuals with disabilities are always encouraged to apply for NIH programs. SPECIAL REQUIREMENTS When clinical studies are a component of the research proposed, studies must be monitored commensurate with the degree of potential risk to study subjects and the complexity of the study. AN UPDATED NIAID policy on the requirements for such monitoring was published in the NIH Guide on July 8, 2002 and is available at: NOT-AI-02-032.html. The full policy, including terms and conditions of award, is available at: WHERE TO SEND INQUIRIES We encourage inquiries concerning this RFA and welcome the opportunity to answer questions from potential applicants. Inquiries may fall into three areas: scientific/research, peer review, and financial or grants management issues: o Direct questions about scientific/research issues to: Helen Quill, Ph.D. Division of Allergy, Immunology and Transplantation National Institute of Allergy and Infectious Diseases Room 1128, MSC-7640 6700-B Rockledge Drive Bethesda, MD 20892-7640 Telephone: (301) 496-7551 FAX: (301) 480-2381 Email: Beena Akolkar, Ph.D. Division of Diabetes, Endocrinology and Metabolism National Institute of Diabetes and Digestive and Kidney Diseases Room 681, MSC-5460 2 Democracy Plaza Bethesda, MD 20892-5460 Telephone: (301) 594-8812 FAX: (301) 480-3503 Email: Judith Massicot-Fisher, Ph.D. Division of Heart and Vascular Diseases National Heart, Lung and Blood Institute Room 9184, MSC-7940 6701 Rockledge Drive Bethesda, MD 20892-7940 Telephone: (301) 435-0528 FAX: (301) 480-1454 Email: o Direct questions about peer review issues to: Dr. Priti Mehrotra Division of Extramural Activities National Institute of Allergy and Infectious Diseases Room 2100, MSC-7616 6700-B Rockledge Drive Bethesda, MD 20892-7616 Telephone: (301) 435-9369 FAX: 301-403-2638 Email: o Direct questions about financial or grants management matters to: Maryellen M. Connell Division of Extramural Activities National Institute of Allergy and Infectious Diseases Room 2123, MSC-7614 6700-B Rockledge Drive Bethesda, MD 20892-7614 Telephone: (301) 402-5576 FAX: (301) 480-3780 Email: LETTER OF INTENT Prospective applicants are asked to submit a letter of intent that includes the following information: o Descriptive title of the proposed research o Name, address, and telephone number of the Principal Investigator o Names of other key personnel o Participating institutions o Number and title of this RFA Although a letter of intent is not required, is not binding, and does not enter into the review of a subsequent application, the information that it contains allows IC staff to estimate the potential review workload and plan the review. The letter of intent is to be sent by the date listed at the beginning of this document. The letter of intent should be sent to: Dr. Priti Mehrotra Division of Extramural Activities National Institute of Allergy and Infectious Diseases Room 2100, MSC-7616 6700-B Rockledge Drive Bethesda, MD 20892-7616 Telephone: (301) 435-9369 FAX: 301-403-2638 Email: SUBMITTING AN APPLICATION Applications must be prepared using the PHS 398 research grant application instructions and forms (rev. 5/2001). The PHS 398 is available at in an interactive format. For further assistance contact GrantsInfo, Telephone (301) 710-0267, Email: SUPPLEMENTAL INSTRUCTIONS SPECIFIC INSTRUCTIONS FOR MODULAR GRANT APPLICATIONS: Applications requesting up to $250,000 per year in direct costs must be submitted in a modular grant format. The modular grant format simplifies the preparation of the budget in these applications by limiting the level of budgetary detail. Applicants request direct costs in $25,000 modules. Section C of the research grant application instructions for the PHS 398 (rev. 5/2001) at includes step-by-step guidance for preparing modular grants. Additional information on modular grants is available at SUPPLEMENTAL INSTRUCTIONS FOR R21 APPLICATIONS: To apply, please follow NIH guidelines for submission of an R21 application as listed below: 1) The description (abstract) must include a brief explanation of the proposed activity, and how it is consistent with the exploratory/development nature of the R21 mechanism as described in this notice. 2) Although preliminary data are neither expected nor required for an R21 application, they may be included. 3) Sections a-d of the Research Plan may not exceed 10 pages, including tables and figures. 4) Appendix materials should be limited, as is consistent with the exploratory nature of the R21 mechanism, and should not be used to circumvent the page limit for the research plan. Copies of appendix material will only be provided to the primary reviewers of the application and will not be reproduced for wider distribution. The following materials may be included in the appendix: o Up to five publications, including manuscripts (submitted or accepted for publication), abstracts, patents, or other printed materials directly relevant to the project. These may be stapled as sets. o Surveys, questionnaires, data collection instruments, and clinical protocols. These may be stapled as sets. o Original glossy photographs or color images of gels, micrographs, etc., provided that a photocopy (may be reduced in size) is also included within the 10-page limit of items a-d of the research plan. Include five collated sets of all appendix material, in the same package with the application, following all copies of the application. Identify each item with the name of the principal investigator. USING THE RFA LABEL: The RFA label available in the PHS 398 (rev. 5/2001) application form must be affixed to the bottom of the face page of the application. Type the RFA number on the label. 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. In addition, the RFA title and number must be typed on line 2 of the face page of the application form and the YES box must be marked. The RFA label is also available at: SENDING AN APPLICATION TO THE NIH: Submit a signed, typewritten original of the application, including the Checklist, and three signed, photocopies, in one package to: Center For Scientific Review 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. Priti Mehrotra Division of Extramural Activities National Institute of Allergy and Infectious Diseases Room 2100, MSC-7616 6700-B Rockledge Drive Bethesda, MD 20892-7616 Bethesda, MD 20817 (for express mail or courier service) APPLICATION PROCESSING: Applications must be received by the application receipt date listed in the heading of this RFA. If an application is received after that date, it will be returned to the applicant without review. The Center for Scientific Review (CSR) will not accept any application in response to this RFA that is essentially the same as one currently pending initial review, unless the applicant withdraws the pending application. However, when a previously unfunded application, originally submitted as an investigator-initiated application, is to be submitted in response to an RFA, it is to be prepared as a NEW application. That is the application for the RFA must not include an Introduction describing the changes and improvements made, and the text must not be marked to indicate the changes. While the investigator may still benefit from the previous review, the RFA application is not to state explicitly how. Although there is no immediate acknowledgement of the receipt of an application, applicants are generally notified of the review and funding assignment within 8 weeks. PEER REVIEW PROCESS Upon receipt, applications will be reviewed for completeness by the CSR and responsiveness by the NIAID. 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, all applications will: o Receive a written critique o Undergo a selection process in which only those applications deemed to have the highest scientific merit, generally the top half of applications under review, will be discussed and assigned a priority score o Receive a second level review by the appropriate council or board. REVIEW CRITERIA The goals of NIH-supported research are to advance our understanding of biological systems, improve the control of disease, and enhance health. In the written comments, reviewers will be asked to discuss the following aspects of the application in order to judge the likelihood that the proposed research will have a substantial impact on the pursuit of these goals: o Significance o Approach o Innovation o Investigator o Environment The scientific review group will address and consider each of these criteria in assigning the application's overall score, weighting them as appropriate for each application. The application does not need to be strong in all categories to be judged likely to have 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. 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? 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? INNOVATION: Does the project employ novel concepts, approaches or methods? Are the aims original and innovative? Does the project challenge existing paradigms or develop new methodologies or technologies? 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)? 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? PROTECTION OF HUMAN SUBJECTS FROM RESEARCH RISK: The involvement of human subjects and protections from research risk relating to their participation in the proposed research will be assessed. (See criteria included in the section on Federal Citations, below). INCLUSION OF WOMEN, MINORITIES AND CHILDREN IN RESEARCH: The adequacy of plans to include subjects from both genders, all racial and ethnic groups (and subgroups), and children as appropriate for the scientific goals of the research. Plans for the recruitment and retention of subjects will also be evaluated. (See Inclusion Criteria in the sections on Federal Citations, below). CARE AND USE OF VERTEBRATE ANIMALS IN RESEARCH: If vertebrate animals are to be used in the project, the five items described under Section f of the PHS 398 research grant application instructions (rev. 5/2001) will be assessed. ADDITIONAL CONSIDERATIONS DATA SHARING: The adequacy of the proposed plan to share data. BUDGET: The reasonableness of the proposed budget and the requested period of support in relation to the proposed research. RECEIPT AND REVIEW SCHEDULE Letter of Intent Receipt Date: June 15, 2003 Application Receipt Date: July 15, 2003 Peer Review Date: November, 2003 Council Review: January, 2004 Earliest Anticipated Start Date: February, 2004 AWARD CRITERIA Award criteria that will be used to make award decisions include: o Scientific merit of the proposed project as determined by peer review o Availability of funds o Programmatic priorities. REQUIRED FEDERAL CITATIONS HUMAN SUBJECTS PROTECTION: Federal regulations (45CFR46) require that applications and proposals involving human subjects must be evaluated with reference to the risks to the subjects, the adequacy of protection against these risks, the potential benefits of the research to the subjects and others, and the importance of the knowledge gained or to be gained. INCLUSION OF WOMEN AND MINORITIES IN CLINICAL RESEARCH: 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 clinical research projects unless a clear and compelling justification is provided indicating that inclusion is inappropriate with respect to the health of the subjects or the purpose of the research. This policy results from the NIH Revitalization Act of 1993 (Section 492B of Public Law 103-43). All investigators proposing clinical research should read the AMENDMENT "NIH Guidelines for Inclusion of Women and Minorities as Subjects in Clinical Research - Amended, October, 2001," published in the NIH Guide for Grants and Contracts on October 9, 2001 ( files/NOT-OD-02-001.html); a complete copy of the updated Guidelines are available at guidelines_amended_10_2001.htm. The amended policy incorporates: the use of an NIH definition of clinical research; updated racial and ethnic categories in compliance with the new OMB standards; clarification of language governing NIH-defined Phase III clinical trials consistent with the new PHS Form 398; and updated roles and responsibilities of NIH staff and the extramural community. The policy continues to require for all NIH-defined Phase III clinical trials that: a) all applications or proposals and/or protocols must provide a description of plans to conduct analyses, as appropriate, to address differences by sex/gender and/or racial/ethnic groups, including subgroups if applicable; and b) investigators must report annual accrual and progress in conducting analyses, as appropriate, by sex/gender and/or racial/ethnic group differences. INCLUSION OF CHILDREN AS PARTICIPANTS IN RESEARCH INVOLVING HUMAN SUBJECTS: The NIH maintains a policy that children (i.e., individuals under the age of 21) must be included in all human subjects research, conducted or supported by the NIH, unless there are scientific and ethical reasons not to include them. This policy applies to all initial (Type 1) applications submitted for receipt dates after October 1, 1998. All investigators proposing research involving human subjects should read the "NIH Policy and Guidelines" on the inclusion of children as participants in research involving human subjects that is available at REQUIRED EDUCATION ON THE PROTECTION OF HUMAN SUBJECT PARTICIPANTS: NIH policy requires education on the protection of human subject participants for all investigators submitting NIH proposals for research involving human subjects. This policy announcement is in the NIH Guide for Grants and Contracts Announcement, dated June 5, 2000, at HUMAN EMBRYONIC STEM CELLS (hESC): Criteria for federal funding of research on hESCs can be found at and at Only research using hESC lines that are registered in the NIH Human Embryonic Stem Cell Registry will be eligible for Federal funding (see It is the responsibility of the applicant to provide the official NIH identifier(s)for the hESC line(s)to be used in the proposed research. Applications that do not provide this information will be returned without review. PUBLIC ACCESS TO RESEARCH DATA THROUGH THE FREEDOM OF INFORMATION ACT: The Office of Management and Budget (OMB) Circular A-110 has been revised to provide public access to research data through the Freedom of Information Act (FOIA) under some circumstances. Data that are (1) first produced in a project that is supported in whole or in part with Federal funds and (2) cited publicly and officially by a Federal agency in support of an action that has the force and effect of law (i.e., a regulation) may be accessed through FOIA. It is important for applicants to understand the basic scope of this amendment. NIH has provided guidance at Applicants may wish to place data collected under this PA in a public archive, which can provide protections for the data and manage the distribution for an indefinite period of time. If so, the application should include a description of the archiving plan in the study design and include information about this in the budget justification section of the application. In addition, applicants should think about how to structure informed consent statements and other human subjects procedures given the potential for wider use of data collected under this award. STANDARDS FOR PRIVACY OF INDIVIDUALLY IDENTIFIABLE HEALTH INFORMATION: The Department of Health and Human Services (DHHS) issued final modification to the "Standards for Privacy of Individually Identifiable Health Information", the "Privacy Rule," on August 14, 2002. The Privacy Rule is a federal regulation under the Health Insurance Portability and Accountability Act (HIPAA) of 1996 that governs the protection of individually identifiable health information, and is administered and enforced by the DHHS Office for Civil Rights (OCR). Those who must comply with the Privacy Rule (classified under the Rule as "covered entities") must do so by April 14, 2003 (with the exception of small health plans which have an extra year to comply). Decisions about applicability and implementation of the Privacy Rule reside with the researcher and his/her institution. The OCR website ( provides information on the Privacy Rule, including a complete Regulation Text and a set of decision tools on "Am I a covered entity?" Information on the impact of the HIPAA Privacy Rule on NIH processes involving the review, funding, and progress monitoring of grants, cooperative agreements, and research contracts can be found at URLs IN NIH GRANT APPLICATIONS OR APPENDICES: All applications and proposals for NIH funding must be self-contained within specified page limitations. Unless otherwise specified in an NIH solicitation, Internet addresses (URLs) should not be used to provide information necessary to the review because reviewers are under no obligation to view the Internet sites. Furthermore, we caution reviewers that their anonymity may be compromised when they directly access an Internet site. HEALTHY PEOPLE 2010: The Public Health Service (PHS) is committed to achieving the health promotion and disease prevention objectives of "Healthy People 2010," a PHS-led national activity for setting priority areas. This PA is related to one or more of the priority areas. Potential applicants may obtain a copy of "Healthy People 2010" at AUTHORITY AND REGULATIONS This program is described in the Catalogue of Federal Domestic Assistance at in the following citations: No. 93.855, Immunology, Allergy, and Transplantation Research; No. 93.856, Microbiology and Infectious Diseases Research; No. 93.847, Diabetes, Endocrinology and Metabolism Research; No. 93.837, Heart and Vascular Diseases Research; and No. 93.838, Lung Diseases Research. Awards are made under authorization of Sections 301 and 405 of the Public Health Service Act as amended (42 USC 241 and 284) and administered under NIH grants policies and Federal Regulations 42 CFR 52 and 45 CFR Parts 74 and 92. This program is not subject to the intergovernmental review requirements of Executive Order 12372 or Health Systems Agency review. The NIH Grants Policy Statement is available at This document includes general information about the grant application and review process; information on the terms and conditions that apply to NIH Grants and cooperative agreements; and a listing of pertinent offices and officials at the NIH. All awards are subject to the terms and conditions, cost principles, and other considerations described in the NIH Grants Policy Statement. The PHS strongly encourages all grant recipients to provide a smoke-free workplace and discourage the 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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