Full Text AI-93-07


NIH GUIDE, Volume 21, Number 45, December 18, 1992

RFA:  AI-93-07

P.T. 34


National Institute of Allergy and Infectious Diseases

Letter of Intent Date:  January 15, 1993
Application Receipt Date:  March 25, 1993


The Division of Allergy, Immunology and Transplantation (DAIT) of the
National Institute of Allergy and Infectious Diseases (NIAID) invites
applications for studies dealing with the mechanisms of peripheral
immunological tolerance and anergy.  Improved knowledge of peripheral
tolerance and anergy is likely to open new avenues to:  treatment or
prevention of a variety of autoimmune and allergic disorders,
moderating organ and bone marrow graft rejection, and vaccination
against infectious organisms.


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 Request
for Applications (RFA), Mechanisms of Peripheral Immunological
Tolerance and Anergy, is related to the priority areas of diabetes
and chronic disabling diseases, and to immunization and infectious
diseases.  Potential applicants may obtain a copy of "Healthy People
2000" (Full Report:  Stock No. 017-001-00474-0) or "Healthy People
2000"  (Summary Report:  Stock No. 017-001-00473-1) through the
Superintendent of Documents, Government Printing Office, Washington,
DC 20402-9325 (telephone 202-782-3238).


Only domestic organizations are eligible to apply.  Applications may
be submitted by domestic 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.  The NIAID encourages the
participation of minorities and women, either as the Program Director
or as project leaders of the component research projects of the


This RFA will use the National Institutes of Health (NIH) Program
Project grant (P01).  A P01 is awarded to an institution on behalf of
a Program Director for the support of a broadly based,
multidisciplinary, long-term research program with a specific major
goal or central theme.  A P01 generally involves the organized
efforts of a group of investigators who conduct research projects
related to the overall program goal.  The grant may provide support
for the projects and for certain central resources shared by
individuals in the P01 if sharing facilitates the total research
effort.  Each project supported under a P01 is expected to contribute
to and be directly related to the central theme of the program.  The
projects, each under the direction of a Project Leader, must
demonstrate an essential element of unity and interdependence.

The application should clearly explain how the projected
multidisciplinary integrated program can be expected to accomplish
the stated goal more efficiently and effectively than could a series
of independent, individual grant-supported studies.

Designation of a Principal Investigator as Program Director must be
based upon accomplishment and experience as a scientist, the ability
to assume both the leadership of the research group and the
responsibility for scientific, professional, and administrative
functions, and the commitment of a significant amount of his/her time
to the project.  Each research project in the program should have a
designated Project Leader with a demonstrable record of
accomplishment in immunology or one of the basic science disciplines
or clinical specialties relevant to the particular subject of
investigation.  However, the NIAID encourages the designation as
Project Leader of one junior investigator whose scientifically
meritorious project is an integral part of the overall program and
whose work would be closely related to that of one or more senior
scientists of the P01.

The total project period for applications submitted in response to
this RFA may not exceed five years.  At this time, the NIAID is
administratively limiting the duration of such grants to four years;
this administrative limitation may change in the future.  The budget
of the P01 application should not exceed $500,000 total direct costs
in the first year and no more than four percent annual inflationary
increases for future years.  Applications with an annual budget
request in excess of this amount will require written approval by
senior NIAID officials via the program officer for acceptance of the
application for processing.


The estimated total funds (direct and indirect costs) available for
the first year of support for this RFA will be $1,500,000.  In Fiscal
Year 1993, the NIAID plans to award at least two program project
grants submitted in response to this RFA and, depending on
availability of funds and scientific merit, possibly more than two.
PHS policies governing grants administration and management will
apply.  This level of support is dependent on the receipt of a
sufficient number of applications of high scientific merit.  Although
this program is provided for in the financial plans of the NIAID,
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.



Tolerance and anergy may be imposed at any of several levels within
the immune system and, while the precise mechanisms may vary,
together these levels probably constitute a hierarchy that is
designed to prevent normal physiological reactions against self from
leading to autoimmune disorders. Thus, tolerance may arise from
clonal deletion of potentially autoaggressive T cells within the
thymus ("ignorance of self").  Alternatively, prospective T cells may
be rendered nonfunctional ("anergic") within the thymus and
subsequently be exported without dying.  Similarly, extrathymic T
cells may be eliminated by programmed cell death or rendered anergic,
although still viable.  Both B and T lymphocytes are susceptible to
the induction of tolerance and anergy.  Because central T cell
nonresponsiveness appears at present to be receiving the most
attention, this RFA is intended to promote research on the mechanisms
leading to clonal deletion and functional inactivation of peripheral
lymphocytes, both B and T.

Research Objectives and Scope

The goal of this program is to gain a comprehensive understanding of
the nature of peripheral tolerance and anergy:  what they are, how
they are induced, and the biochemical and molecular genetic events
involved in inducing and maintaining them.  Studies that involve
humans and human tissues and cells, are especially encouraged.  The
following are some examples of the questions about T lymphocytes that
need to be addressed:

o  What are the elements (e.g., types of interacting cells, surface
molecules, cytokines) and mechanisms involved in T cell tolerance and
anergy that operate extrathymically?

o  Do the mechanisms that lead to tolerance and anergy differ
depending on the tolerizing/anergizing stimulus?  For example, would
the mechanisms differ if a convential antigen or a super-antigen were
involved or if the stimulus were a free peptide compared to a Class
II-peptide complex?

o  What roles are played by the Ti-CD3 complex or by CD4 and CD8
accessory molecules in the induction of T cell tolerance?

o  Are CD4+ and CD8+ T cells distinguishable in their susceptibility
to the induction of tolerance and anergy?

o  What are the different roles played by TH1 and TH2 cells and the
spectra of cytokines that they secrete in the induction and
maintenance of tolerance and anergy?

The following are some examples of the questions about B lymphocytes
that need to be addressed:

o  What is the importance of the density, distribution, affinity and
isotype of membrane-bound antibody molecules?

o  Is B-cell anergy associated with the absence of stimuli/signals
that would otherwise lead to B-cell activation and, if so, what is
the nature of such stimuli?

o  What is the importance of the differentiative status of B cells in
terms of the induction of tolerance and anergy?

The prospects of important clinical applications calls for a
concerted effort to acquire better understanding of these phenomena.



NIH policy requires that applicants for NIH clinical research grants
and cooperative agreements include minorities and women in study
populations so that research findings can be of benefit to all
persons at risk of the disease, disorder or condition under study;
special emphasis must be placed on the need for inclusion of
minorities and women in studies of diseases, disorders and conditions
which disproportionately affect them.  This policy is intended to
apply to males and females of all ages.  If women or minorities are
excluded or inadequately represented in clinical research,
particularly in proposed population-based studies, a clear compelling
rationale MUST be provided.

The composition of the proposed study population must be described in
terms of gender and racial/ethnic group, together with a rationale
for its choice.  In addition, gender and racial/ethnic issues should
be addressed in developing a research design and sample size
appropriate for the scientific objectives of the study.  This
information should be included in the form PHS 398 in items 1-4 of
the Research Plan AND summarized in item 5, Human Subjects.

Applicants are urged to assess carefully the feasibility of including
the broadest possible representation of minority groups.  However,
NIH recognizes that it may not be feasible or appropriate in all
research projects to include representation of the full array of
United States racial/ethnic minority populations [i.e., Native
Americans (including American Indians or Alaskan Natives),
Asian/Pacific Islanders, Blacks, Hispanics].  The rationale for
studies on single minority population groups should be provided.

For the purpose of this policy, clinical research includes human
biomedical and behavioral studies of etiology, epidemiology, (and
preventive strategies), diagnosis, or treatment of diseases,
disorders or conditions, including but not limited to, clinical

The usual NIH policies concerning research on human subjects also
apply. Basic research or clinical studies in which human tissues
cannot be identified or linked to individuals are excluded.  However,
clinical samples which may be coded for use by the applicant but
could be identified by another source are not excluded.  Every effort
should be made and documented to include human tissues from women and
racial/ethnic minorities when it is important to apply the results of
the study broadly, and this should be addressed by applicants.

If the required information is not contained within the application,
the application will be returned.

Peer reviewers will address specifically whether the research plan in
the application conforms to these policies.  If the representation of
women or minorities in a study design is inadequate to answer the
scientific question(s) addressed AND the justification for the
selected study population is inadequate, it will be considered a
scientific weakness or deficiency in the study design and will be
reflected in assigning the priority score to the application.

All applications for clinical research submitted to NIH are required
to address these policies.  NIH funding components will not award
grants or cooperative agreements that do not comply with these


Prospective applicants are asked to submit, by January 15, 1993, a
letter of intent that includes a descriptive title of the overall
proposed research, the name, address and telephone number of the
Principal Investigator (Program Director), the names of key
investigators, 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. Mark Rohrbaugh at the address listed


Applications are to be submitted on the standard research grant
application form PHS 398 (rev. 09/91).  Item 2a on the face page of
the application must be marked "yes" and the RFA number and the words
typed in.

These application forms may be obtained from the institution's office
of sponsored research and from the Office of Grants Inquiries,
Division of Research Grants, National Institutes of Health, 5333
Westbard Avenue, Room 449, Bethesda, Maryland 20892, telephone (301)

It is highly recommended that the Chief of the Basic Immunology
Branch or the Chief of the Immunoregulation Section be contacted in
the early stages of preparation of the application.

Applications must be received by March 25, 1993.  Applications that
are not received by the receipt date or that do not conform to the
instructions contained in PHS 398 (rev. 09/91) application kit, will
be judged non-responsive and will be returned to the applicant.

The RFA label available in the application form 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.

Submit a signed, typewritten original of the application, including
the checklist, and three signed, exact, single-sided photocopies, in
one package to:

Application Receipt Office
Division of Research Grants
National Institutes of Health
Westwood Building, Room 240
Bethesda, MD  20892**

At the time of submission, two additional exact copies of the
application must also be sent to Dr. Mark Rohrbaugh at the address


General review considerations are outlined in the NIAID Information
Brochure on Program Project and Center Grants, which contains special
instructions for preparing multiproject applications for Program
Projects.  It includes REVIEW PROCEDURES and REVIEW CRITERIA for
multicomponent, interdisciplinary projects and other important
information.  This Information Brochure and the RFA will be sent to
applicants upon request.

Upon receipt, applications will be reviewed for completeness by the
Division of Research Grants (DRG) and for responsiveness by NIAID
staff; those judged to be incomplete or non-responsive will be
returned to the applicant without review.

Those applications that are complete and responsive may be subjected
to a triage by an NIAID peer review group before or during the
scientific review meeting to determine their scientific merit
relative to other applications received in response to this RFA.  The
NIAID will withdraw from competition those applications judged to be
non-competitive for award and will notify the applicant and
institutional business officials.

Those applications judged by the reviewers to be competitive for
award will be further reviewed for scientific and technical merit by
a review committee convened by the Division of Extramural Activities,
NIAID.  The second level of review will be provided by the National
Advisory Allergy and Infectious Diseases Council.

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 the Principal Investigator of the GCRC must
be included with the application.

Review Criteria

The general criteria are those review criteria for large,
multicomponent, interdisciplinary program projects as outlined in the
NIAID Brochure on Project Project and Center Grants.


Funding decisions will be made on the basis of scientific and
technical merit as determined by peer review, program needs and
balance, and the availability of funds.


Written and telephone inquiries concerning this RFA are encouraged.
The opportunity to clarify any issues or questions from potential
applicants is welcome.

Direct inquiries about the RFA and programmatic issues to:

Joseph F. Albright, Ph.D. or M. Michele Hogan, Ph.D.
Division of Allergy, Immunology and Transplantation
National Institute of Allergy and Infectious Diseases
Solar Building, Room 4A22
Bethesda, MD  20892
Telephone:  (301) 496-7551
FAX:  (301) 402-0175

Direct inquiries regarding review issues, and address the letter of
intent to:

Mark Rohrbaugh, Ph.E., Scientific Review Administrator
Microbiology and Immunology Review Section
Division of Extramural Activities
National Institute of Allergy and Infectious Diseases
Solar Building, Room 4C22
Bethesda, MD  20892
Telephone:  (301) 496-8424
FAX:  (301) 402-2638

Direct inquiries regarding fiscal matters to:

Mr. Jeffrey Carow
Chief, Immunology Grants Management Section
Division of Extramural Activities
National Institute of Allergy and Infectious Diseases
Solar Building, Room 4B92
Bethesda, MD  20892
Telephone:  (301) 496-7075

The mailing address for sending applications to NIAID staff in the
Building is the central mailing address for NIH.  Applicants who use
mail or a courier service are advised to follow the carrier's
requirements for
showing a street address.  The address for the Solar Building is:

6003 Executive Boulevard
Rockville, MD  20852


Letter of Intent Date:     January 15, 1993
Application Receipt Date:  March 25, 1993
Scientific Review Date:    June 1993
Advisory Council Date:     September 1993
Earliest Award Date:       September 1993


This program is described in the Catalog of Federal Domestic
Assistance, No. 93.855 - Immunology, Allergy and Transplantation
Research.  Awards will be made under the authority of the Public
Health Service Act, Title III, Section 301 (Public Law 78-410, as
amended; 42 USC 241) and administered under PHS grants policies and
Federal Regulations 42 CFR Part 74.  This program is not subject to
the intergovernmental review requirements of Executive Order 12372 or
Health Systems Agency review.


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