Full Text AI-93-10

MECHANISMS OF ORAL TOLERIZATION AND IMMUNIZATION

NIH GUIDE, Volume 22, Number 10, March 12, 1993

RFA:  AI-93-10

P.T. 34

Keywords: 
  Biology, Cellular 
  Biology, Molecular 
  Vaccine 
  Immunology 
  Genetics 


National Institute of Allergy and Infectious Diseases
National Institute of Arthritis and Musculoskeletal and Skin Diseases

Letter of Intent Receipt Date:  April 5, 1993
Application Receipt Date:  July 21, 1993

PURPOSE

The Division of Allergy, Immunology and Transplantation (DAIT) of the
National Institute of Allergy and Infectious Diseases (NIAID) and the
Rheumatic Diseases Branch of the National Institute of Arthritis and
Musculoskeletal and Skin Diseases (NIAMS) invite applications for
studies focused on cellular and molecular mechanisms of oral
immunization and oral tolerance.  The goal of this initiative is to
promote research that will increase our understanding of the
mechanisms involved in the induction of protective immunity
systemically and in the mucosal surfaces after oral immunization and
improve our knowledge about the effects of oral administration of
self-molecules as a means of inducing tolerance to prevent or reverse
autoimmune and allergic diseases.

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 Request
for Applications (RFA), Mechanisms of Oral Tolerization and
Immunization, is related to the priority areas of diabetes and
chronic disabling conditions, and 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).

ELIGIBILITY REQUIREMENTS

Applications may be submitted by public and private, foreign and
domestic, for-profit and non-profit organizations, such as
universities, colleges, hospitals, laboratories, units of State and
local governments, and eligible agencies of the Federal government.
Only domestic institutions are eligible to apply for Program Project
(P01) grants.  Women and minority investigators are encouraged to
apply.

MECHANISM OF SUPPORT

The mechanisms of support for this program will be the research
project grant (R01) and the Program Project (P01) grant.  The
regulations and policies that govern the research grant programs of
the National Institutes of Health will prevail.  Responsibility for
the planning, direction, and execution of the proposed project will
be solely that of the applicant.

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 P01 grants to four years;
this administrative limitation may change in the future.  P01
applications may not request budgets in excess of $500,000, and R01
applications, $180,000, total direct costs in the first year; neither
type of application should request more than 4 percent annual
inflationary increases for future years.  An application with a first
year requested amount in excess of the above will require written
approval by senior NIAID or NIAMS officials via the program officers
for acceptance of the application for processing.

FUNDS AVAILABLE

The estimated total funds (direct and indirect) available for the
first year of support for this RFA will be $1,500,000.  In fiscal
year 1994, the NIAID plans to fund approximately seven research
projects, either as R01s or as components of P01s.  In fiscal year
1994, the NIAMS plans to fund approximately three R01s.  The usual
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 and
the NIAMS, 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.

RESEARCH OBJECTIVES

Background

Mucosal surfaces are the most common portals of entry of
microorganisms and other environmental factors, and effective immune
mechanisms exist that afford protection against some of the diseases
caused by these organisms.  In addition, protective immune responses
can be induced in external secretions by oral administration of some
attenuated or killed organisms.  Although progress has been made in
understanding the composition and some of the functions of the
mucosal immune system in the induction of protective immunity, the
basic mechanisms and molecular mediators involved in the development
of immune responses remain largely unknown.  Knowledge of the basic
cellular and molecular immune mechanisms of the gastrointestinal
tract will be the foundation for the development of successful
multicomponent oral vaccines and oral tolerization protocols, and an
understanding of inflammatory bowel disease.

Experimental autoimmune diseases such as collagen-induced arthritis,
experimental allergic encephalomyelitis and experimental uveitis have
been successfully treated by the oral administration of the relevant
antigen. Evidence suggests that a subpopulation of T cells and
cytokines, such as TGF beta, are implicated in the induction of
tolerance and prevention and/or delay of disease onset.  However, the
molecular basis for oral tolerance induction to autoantigens and the
mechanisms that govern these processes are not understood.  Although
results obtained in experimental systems are encouraging, it is not
clear whether oral tolerance regimens in established disease suppress
or exacerbate autoimmune conditions.  Carefully controlled studies
using well defined self peptides and antigens in combination with
advanced molecular and cellular immunology approaches are necessary
before oral tolerance is considered as an effective form of therapy
for human disease.

Research Objectives and Scope

Areas of interest include, but are not limited to:

o  Studies of the mechanisms involved in the induction and regulation
of oral tolerance to self antigens, with emphasis on the
identification of the cell types and cytokine cascades involved.

o  Analysis of the effect of oral administration of self peptides on
ongoing autoimmune disease and the cellular and molecular mechanisms
that mediate these effects.

o  Characterization of the molecular basis for the observed decrease
in tissue damage in organ-specific autoimmune disease following the
oral administration of appropriate antigens.

o  Studies to establish the immune parameters of induction of
protective immune responses to orally administered antigens including
attenuated or killed enteric pathogens, with emphasis on the
characterization of cellular and molecular mediators involved in
these processes.

o  Studies to analyze and determine peripheral and/or systemic
correlates of protective immunity to orally administered antigens,
including enteric pathogens and antigens delivered in carrier
systems.

o  Studies of antigen processing and presentation by gut epithelial
and lymphoid cells and design of methodologies to manipulate them to
obtain stronger and/or long lasting protective immunity.

New approaches to the study of mucosal immunity and approaches that
combine cellular and molecular immunology and bacterial genetics are
strongly encouraged as are studies that would yield information
directly applicable to the human mucosal system/autoimmune disease
interface.

STUDY POPULATIONS

SPECIAL INSTRUCTIONS TO APPLICANTS REGARDING IMPLEMENTATION OF NIH
POLICIES CONCERNING INCLUSION OF WOMEN AND MINORITIES IN CLINICAL
RESEARCH STUDY POPULATIONS

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 must 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 U.S.
racial/ethnic minority populations [i.e., Native Americans (including
American Indians or Alaskan Natives), Asian/Pacific Islanders,
Blacks, and Hispanics].  The rationale for studies on single minority
population groups should be provided.

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

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.

For foreign awards, the policy on inclusion of women applies fully;
since the definition of minority differs in other countries, the
applicant must discuss the relevance of research involving foreign
population groups to the U.S. populations, including minorities.

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
policies.

Previous recruitment data for similar studies from the proposed sites
should be provided.

LETTER OF INTENT

Prospective applicants are asked to submit, by April 5, 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 or Program Director (for P01s), 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 and NIAMS
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 under INQUIRIES.

APPLICATION PROCEDURES

In preparing the application in response to this RFA, the applicant
should bear in mind the research objectives of this RFA.  An R01
application should be prepared according to the instructions in form
PHS 398 (rev. 9/91).  A P01 application should be prepared using the
guidance and instructions provided in the NIAID document titled:
"SPECIAL INSTRUCTIONS FOR PREPARING THE GROUP APPLICATION FOR PROGRAM
PROJECTS."  This document cannot be transmitted electronically,
particularly Tables I-IV which may be used by the applicant for
appropriate and consistent presentation of summary information on
budgets and personnel.  The P01 applicant should request and obtain a
copy of such document and a copy of the NIAID Information Brochure
for Program Projects and Grants, both of which may be sent along with
this RFA.  Failure to follow the instructions in the document may
result in delays in the review or in an incomplete application.

Applications are to be submitted on the standard research grant
application form PHS 398 (rev. 09/91).  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, MD 20892, telephone (301) 496-7441.

For purposes of identification and processing, item 2a on the face
page of the application must be marked "Yes" and the RFA number and
the words "MECHANISMS OF ORAL TOLERIZATION AND IMMUNIZATION" must be
entered.

Applications must be received by July 21, 1993. Applications that are
not received from the applicant organization by the receipt date or
that do not conform to the instructions contained in PHS 398 (rev.
09/91) application kit, will be judged to be 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.

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 grant
application and all five sets of appendix material must also be sent
to Dr. Mark Rohrbaugh 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.  In such a case, a letter of agreement from
either the GCRC Program Director or Principal Investigator should be
included with the application.

REVIEW CONSIDERATIONS

Upon receipt, applications will be reviewed for completeness by the
Division of Research Grants (DRG) and by NIAID and NIAMS staff for
responsiveness.  Those judged to be incomplete will be returned to
the applicant without review.  Those considered to be non-responsive
will be either returned without review or, if R01s, be referred to
the DRG as unsolicited applications, to be scheduled for initial
review at the next DRG review cycle.

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

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 Scientific Review Branch, Division
of Extramural Activities, NIAID.  The second level of review will be
provided by the National Advisory Allergy and Infectious Diseases
Council or by the National Arthritis and Musculoskeletal and Skin
Diseases Council.
The factors to be considered in the evaluation of scientific merit of
each application will be those used in the review of traditional
research project grant applications, including:  the novelty,
originality, and feasibility of the approach; the training,
experience, and research competence of the investigator(s); the
adequacy of the experimental design; and the adequacy and suitability
of the facilities.  For program project applications, additional
review criteria are used, which are outlined in the NIAID Information
Brochure on Program Project and Center Grants.  Applicants planning a
program project application must request and obtain the NIAID
Information Brochure.

While the following review factors do not usually influence the
priority score, they are nonetheless carefully considered by the
initial review group: the appropriateness of the requested budget to
the work proposed; the adequacy of protection of human subjects
and/or animals in research; and the adherence, whenever appropriate,
to NIH guidelines concerning adequate representation of women and
minorities in clinical research.  Any documented concerns expressed
by the initial review group about any of these factors on a given
application may influence the recommendation of the Advisory Council
concerning funding of that application.

AWARD CRITERIA

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.

INQUIRIES

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

Direct requests for the Information Brochure and the documents
referred to under APPLICATION PROCEDURES, as well as inquiries
regarding programmatic issues, to:

Howard B. Dickler, M.D.
Division of Allergy, Immunology, and Transplantation
National Institute of Allergy and Infectious Diseases
Solar Building, Room 4A19
Bethesda, MD  20892
Telephone:  (301) 496-7104
FAX:  (301) 402-2571

Susan Serrate-Sztein, M.D.
Rheumatic Diseases Branch
National Institute of Arthritis and Musculoskeletal Diseases
Westwood Building, Room 405
Bethesda, MD  20892
Telephone:  (301) 402-3340
FAX:  (301) 480-7881

Direct inquiries regarding review issues (including the preparation
of a program project application if applicable); address the letter
of intent to; and mail two copies of the application and all five
sets of appendices to:

Mark Rohrbaugh, Ph.D.
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 and administrative matters to:

Mr. Jeffrey Carow
Division of Extramural Activities
National Institute of Allergy and Infectious Diseases
Solar Building, Room 4B29
Bethesda, MD  20892
Telephone:  (301) 496-7075

The mailing address given for NIAID staff in the Solar Building is
the
central mailing address for NIH.  Applicants who use express 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

Schedule

Letter of Intent Receipt Date:  April 5, 1993
Application Receipt Date:       July 21, 1993
Scientific Review Date:         October 1993
Advisory Council Date:          February 1994
Earliest Award Date:           April 1994

AUTHORITY AND REGULATIONS

This program is described in the Catalog of Federal Domestic
Assistance, No. 93.855 - Immunology, Allergy and Transplantation
Research and No. 93.846 - Arthritis and Musculoskeletal and Skin
Diseases 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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