Release Date:  February 9, 2000

RFA:  AI-00-006

National Institute of Allergy and Infectious Diseases
National Institute of Diabetes and Digestive and Kidney Diseases

Letter of Intent Receipt Date: August 1, 2000
Application Receipt Date:  September 14, 2000



The National Institute of Allergy and Infectious Diseases (NIAID) and 
the National Institute of Diabetes and Digestive and Kidney Diseases 
(NIDDK), 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.


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 Request for 
Applications (RFA), “Innovative Grants on Immune Tolerance”, is related 
to the priority areas of Immunization and Infectious Diseases and 
Diabetes and Chronic Diseases. Potential applicants may obtain a copy 
of "Healthy People 2010" at <>.


Applications may be submitted by domestic and foreign, 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.  
Racial/ethnic minority individuals, women, and persons with 
disabilities are encouraged to apply as Principal Investigators.


Specific application instructions have been modified to reflect 
“MODULAR GRANT” and “JUST-IN-TIME” streamlining efforts being examined 
by the NIH. Complete and detailed instructions on Modular Grant 
applications can be found at

The mechanism of support will be the Exploratory/Developmental Research 
Project Grant (R21).  The total project period for an application 
submitted in response to this RFA may not exceed 3 years. 
Responsibility for the planning, direction, and execution of the 
proposed project will be solely that of the applicant.
NIH uses R21 grants to provide short-duration support for preliminary 
studies of a highly speculative nature, which are expected to yield, 
within a two- or three-year time frame, sufficient information upon 
which to base a well-planned and rigorous series of further 

This RFA is a one-time solicitation.  Future unsolicited competing 
continuation applications will compete with all investigator-initiated 
applications and be reviewed according to the customary peer review 
procedures.  The earliest anticipated award date is July, 2001.


The estimated total funds (direct and facilities and administrative 
[F&A] costs) available for the first year of support will be $1.7 
million from NIAID.  In FY 2001, the NIAID plans to fund approximately 
eight to ten awards. NIDDK will provide $1.0 million in FY 2001, to 
fund approximately 4-5 applications relevant to diseases within the 
mission of the NIDDK. An applicant may request a project period of up 
to three years and a budget for direct costs of up to $150,000 per 
year, excluding F&A costs or consortium arrangements. Although this 
program is provided for in the financial plans of the NIH, awards 
pursuant to this RFA are contingent upon the availability of funds and 
the receipt of a sufficient number of applications of outstanding 
scientific and technical merit. 



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.  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, or tolerance induction. 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 disease and organ transplantation.  There is still a strong 
need to develop new concepts and practical approaches for tolerance 
induction, because it is likely that a variety of protocols will be 
needed to control the broad range of immune-mediated diseases that 
exist in humans.

Immune-mediated diseases afflict millions of individuals and often 
involve serious recurring or long-term chronic illness.  As highlighted 
by recent success in inducing long-term transplant tolerance in non-
human primates, very 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 disease and transplantation.  The 
application of new technologies such as soluble MHC-peptide reagents, 
the ability to conduct single cell assays, 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 clinical 

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.  
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.  Studies relevant to the etiology and/or treatment of Type 1 
Diabetes are of particular interest to the NIDDK. Studies on HIV/AIDS 
are excluded from this program.  Exploratory/developmental research 
grants (R21) will be used to provide funds to develop preliminary 
studies of a very speculative nature. Within a two- or three-year 
funding period, it is expected that successful projects will yield 
sufficient data to support a well-planned and rigorous future grant 
application to continue the work by competing within the general pool 
of unsolicited applications.

Highly innovative, short-term pilot projects to evaluate new, but as 
yet speculative, 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 or B cell 
molecular targets for tolerance induction;

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 

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 maintain immune 

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.


It is the policy of the NIH that women and members of minority groups 
and their subpopulations 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 policy results from the 
NIH Revitalization Act of 1993 (Section 492B of Public Law 103-43)
All investigators proposing research involving human subjects should 
read the "NIH Guidelines for Inclusion of Women and Minorities as 
Subjects in Clinical Research," which was published in the Federal 
Register of March 28, 1994 (FR 59 14508-14513) and in the NIH Guide for 
Grants and Contracts, Vol. 23, No. 11, March 18, 1994, available on the 
web at: 


It is the policy of NIH 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 was published in 
the NIH Guide for Grants and Contracts, March 6, 1998, and is available 
at the following URL address: 

Investigators also may obtain copies of these policies from the program 
staff listed under INQUIRIES. Program staff may also provide additional 
relevant information concerning the policy.


Prospective applicants are asked to submit, by August 1, 2000, a letter 
of intent that includes a descriptive title of the proposed research; 
the name, address, and telephone number of the Principal Investigator; 
the identities of other key personnel and participating institutions; 
and the number and title of this RFA. Although a 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 a subsequent 
application, the information that it contains allows IC staff to 
estimate the potential review workload and avoid conflict of interest 
in the review. The letter of intent is to be sent (e-mail, fax or post) 
to Dr. Nasrin Nabavi at the address listed under INQUIRIES.


Applicants are strongly encouraged to call NIAID or NIDDK program staff 
with any questions regarding the responsiveness of their proposed 
project to the goals of this RFA.  

The modular grant concept establishes specific modules in which direct 
costs may be requested as well as a maximum level for requested 
budgets. Only limited budgetary information is required under this 
approach.  The just-in-time concept allows applicants to submit certain 
information only when there is a possibility for an award. It is 
anticipated that these changes will reduce the administrative burden 
for the applicants, reviewers and Institute staff.  

The research grant application form PHS 398 (rev. 4/98) is to be used 
in applying for these grants, with the modifications, including a 15-
page limit for the research plan, noted below.


Modular Grant applications will request direct costs in $25,000 
modules. R21 applications may request an annual maximum direct cost of 
$150,000, and may be for up to two or three years. 

For modular grant applications, the total direct costs must be 
requested in accordance with the program guidelines and the 
modifications made to the standard PHS 398 application instructions 
described below:

PHS 398

o FACE PAGE: Items 7a and 7b should be completed, indicating Direct 
Costs (in $25,000 increments up to a maximum of $150,000) and Total 
Costs [Modular Total Direct plus Facilities and Administrative (F&A) 
costs] for the initial budget period. Items 8a and 8b should be 
completed indicating the Direct and Total Costs for the entire proposed 
period of support.

Page 4 of the PHS 398. It is not required and will not be accepted with 
the application.

the categorical budget table on Form Page 5 of the PHS 398. It is not 
required and will not be accepted with the application.

o NARRATIVE BUDGET JUSTIFICATION - Prepare a Modular Grant Budget 
Narrative page. (See for sample 
pages.) At the top of the page, enter the total direct costs requested 
for each year.  This is not a Form page.

o Under Personnel, list key project personnel, including their names, 
percent of effort, and roles on the project. No individual salary 
information should be provided. However, the applicant should use the 
NIH appropriation language salary cap and the NIH policy for graduate 
student compensation in developing the budget request.

For Consortium/Contractual costs, provide an estimate of total costs 
(direct plus facilities and administrative) for each year, each rounded 
to the nearest $1,000. List the individuals/organizations with whom 
consortium or contractual arrangements have been made, the percent 
effort of key personnel, and the role on the project. Indicate whether 
the collaborating institution is foreign or domestic. The total cost 
for a consortium/contractual arrangement is included in the overall 
requested modular direct cost amount. Include the Letter of Intent to 
establish a consortium.

Provide an additional narrative budget justification for any variation 
in the number of modules requested.

o BIOGRAPHICAL SKETCH - The Biographical Sketch provides information 
used by  reviewers in the assessment of each individual's 
qualifications for a specific role in the proposed project, as well as 
to evaluate the overall qualifications of the research team. A 
biographical sketch is required for all key personnel, following the 
instructions below. No more than three pages may be used for each 
person. A sample biographical sketch may be viewed at:
- Complete the educational block at the top of the form page;
- List position(s) and any honors;
- Provide information, including overall goals and responsibilities, on 
research projects ongoing or completed during the last three years.
- List selected peer-reviewed publications, with full citations.

o RESEARCH PLAN – The research plan (a-d) is limited to 15 pages. 
Applications that exceed the page limit will be returned without 
review. An appendix may be included in the application; however, the 
appendix is not to be used to circumvent the page limit of the research 

o CHECKLIST - This page should be completed and submitted with the 
application. If the facilities and administration (F&A) rate agreement 
has been established, indicate the type of agreement and the date. All 
appropriate exclusions must be applied in the calculation of the F&A 
costs for the initial budget period and all future budget years.

o The applicant should provide the name and phone number of the 
individual to contact concerning fiscal and administrative issues if 
additional information is necessary following the initial review. 

Applications are to be submitted on the grant application form PHS 398 
(rev. 4/98). These forms are available at most institutional offices of 
sponsored research; from the Division of Extramural Outreach and 
Information Resources, National Institutes of Health, 6701 Rockledge 
Drive, MSC 7910, Bethesda, MD 20892-7910, telephone 301/710-0267, 
email:; and on the internet at

For purposes of identification and processing, item 2a on the face page 
of the application must be marked "YES" and the RFA number "AI-00-006" 
and the words "INNOVATIVE GRANTS ON IMMUNE TOLERANCE" must be entered 
on the face page.

The RFA label and line 2 of the application should both indicate the 
RFA number.  The RFA label 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.

The sample RFA label available at: has been 
modified to allow for this change.  Please note this is in pdf format.

Applications must be received by September 14, 2000. Applications not 
received as a single package on the receipt date or not conforming to 
the instructions contained in PHS 398 (rev. 4/98) Application Kit (as 
modified in, and superseded by, the special instructions below, for the 
purposes of this RFA), will be judged non-responsive and will be 
returned to the applicant. 

If the application submitted in response to this RFA is substantially 
similar to a grant application already submitted to the NIH for review, 
but that has not yet been reviewed, the applicant will be asked to 
withdraw either the pending application or the new one.  Simultaneous 
submission of identical applications will not be allowed, nor will 
essentially identical applications be reviewed by different review 
committees.  Therefore, an application that is essentially identical to 
one that has already been reviewed cannot be submitted in response to 
this RFA.  This does not preclude the submission of substantial 
revisions of applications already reviewed, but such applications must 
include an introduction addressing the previous critique.

Submit a signed, typewritten original of the application, including the 
checklist, and three signed, exact, single-sided 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 mail or 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. Nasrin Nabavi at the address listed under INQUIRIES.

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 should be included with the 


Upon receipt, applications will be reviewed for completeness by the NIH 
Center for Scientific Review and for responsiveness by NIAID staff; 
those judged to be incomplete or not in the format specified in this 
RFA will be returned to the applicant without review. Those considered 
to be non-responsive will be returned without review.

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 NIAID in accordance with the review criteria 
stated below.  As part of the initial merit review, a process will be 
used by the initial review group in which all applications will receive 
a written critique but only those applications deemed to have the 
highest scientific merit will be discussed, assigned a priority score, 
and receive a second level review by the National Advisory Councils of 
the NIAID and NIDDK.

Review Criteria

The five criteria to be used in the evaluation of grant applications 
are listed below.  To put those criteria in context, the following 
information is contained in instructions to the peer reviewers.

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 

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?

In addition to the above criteria, in accordance with NIH policy, all 
applications will also be reviewed with respect to the following:

o  The adequacy of plans to include both genders, minorities and their 
subgroups, and children as appropriate for the scientific goals of the 
research.  Plans for the recruitment and retention of subjects will 
also be evaluated.

o  The reasonableness of the proposed budget and duration in relation 
to the proposed research

o  The adequacy of the proposed protection for humans, animals or the 
environment, to the extent they may be adversely affected by the 
project  proposed in the application

The personnel category will be reviewed for appropriate staffing based 
on the requested percent effort. The direct costs budget request will 
be reviewed for consistency with the proposed methods and specific 
aims. For modular grant applications, any budgetary adjustments 
recommended by the reviewers will be in $25,000 modules. The duration 
of support will be reviewed to determine if it is appropriate to ensure 
successful completion of the requested scope of the project.

Award criteria that will be used to make award decisions include:
o scientific merit (as determined by peer review)
o availability of funds
o programmatic priorities


Inquiries concerning this RFA are encouraged. The opportunity to 
clarify any issues or questions from potential applicants is welcome.
Direct inquiries regarding programmatic issues to:

Helen Quill, Ph.D.
Division of Allergy, Immunology and Transplantation
National Institute of Allergy and Infectious Diseases
6700-B Rockledge Dr., Room 5140
Bethesda, MD 20892-7640
Telephone: (301) 496-7551
FAX: (301) 402-2571

Barbara Linder, M.D., Ph.D.
Division of Diabetes, Endocrinology and Metabolic Diseases
National Institute of Diabetes and Digestive and Kidney Diseases
Building 45, Room 5AN18A
Bethesda, MD 20892
Telephone: (301) 594-0021
Fax: (301) 480-3503

Direct review inquiries to:

Nasrin Nabavi, Ph.D.
Scientific Review Program, 
Division of Extramural Activities, NIAID
6700-B Rockledge Dr., Room 2212, MSC 7616
Bethesda, MD 20892-7616
Telephone: (301) 435-3567
Fax: (301) 402-2638

Direct inquiries regarding fiscal matters to:

Ms. Pamela Fleming
Grants Management Specialist
Division of Extramural Activities, NIAID
6700-B Rockledge Dr., Room 2119, MSC 7614
Bethesda, MD 20892-7614
Telephone: (301) 402-6580
FAX: (301) 480-3708


Letter of Intent Receipt Date:    August 1, 2000
Application Receipt Date:         September 14, 2000
Peer Review Date:                 January, 2001
Council Review:                   June, 2001
Earliest Anticipated Start Date:  July, 2001


This program is described in the Catalogue of Federal Domestic Health 
Service Act, Sections 93.856, Microbiology and Infectious Diseases 
Research, No. 93.855 - Immunology, Allergy, and Transplantation 
Research and 93.847 – Diabetes, Endocrinology and Metabolism Research.  
Awards will be made under the PHS Act Sections 301 & 405 as amended,(42 
USC 241 & 284) and administered under NIH grants policies and Federal 
Regulations 42 CFR Part 52 and 45 CFR Part 74 & 92.  This program is 
not subject to the intergovernmental review requirements of Executive 
Order 12372 or Health Systems review.

The Public Health Service 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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