Subject: RFA HL-90-14-B.082490
From: Dot Baker <[email-masked]>
To: [email-masked]
Date: Thu, 23 Aug 90 08:04 EST

Hello,
   This is another article to be posted to the NIH Listserver.  Please
post this one as:
                 RFAHL-90-14-B.082490
  Thanks.
         Dottie
 ---------------------------- Text of forwarded message -----------------------
 
REQUEST FOR RESEARCH GRANT APPLICATIONS:
RFA:  HL-90-14-B
 
MOLECULAR BIOLOGICAL TECHNIQUES FOR STUDYING CLASS I AND II
HLA ANTIGENS
 
P.T. 34; K.W. 1002008, 0710070, 0745065
 
NATIONAL HEART, LUNG, AND BLOOD INSTITUTE
 
Letter of Intent Receipt Date:  September 18, 1990
Application Receipt Date:  November 29, 1990
 
PURPOSE
 
The Division of Blood Diseases and Resources (DBDR), National Heart,
Lung, and Blood Institute (NHLBI), invites grant applications for a
single competition to support research and development to:  (1)
apply molecular biological techniques to the determination
of HLA class I and class II alleles; (2) compare these
type designations with the currently used serological
results; and (3) emphasize especially the application of
these procedures to the HLA class I and II typing of minority
population groups.
 
DISCIPLINES AND EXPERTISE
 
Among the disciplines and expertise that may be appropriate
for this program are tissue and leukocyte immunology, nucleic
acid molecular biology, transplantation immunology,
hematology, and bone marrow transplantation biology.
 
ADMINISTRATIVE BACKGROUND
 
The DBDR designs
and administers programs for research in hematology,
transfusion medicine, and marrow transplantation.  The Blood
Resources Branch, DBDR, is responsible for supporting a broad
spectrum of research in transfusion medicine, related areas
involved in transfusion safety, and in marrow
transplantation, especially with regard to unrelated-donor
marrow transplants.  Understanding and applying molecular
biology principles to HLA typing is a goal important to the
NHLBI.
 
SCIENTIFIC BACKGROUND
 
Although the HLA system is of importance to all tissue and
organ transplantation, understanding histocompatibility and
the major histocompatibility genes is especially critical for
bone marrow
transplantation.  Not only should the recipient not reject
the graft (graft failure) but also the patient's life may be
endangered by the graft rejecting the host (graft-vs-host
disease; GVH).  As a further complication, mild chronic GVH
disease may have an anti-leukemia effect (GVL) and be needed
for prolonged disease-free survival when the purpose of the
marrow transplant is to treat leukemia.  GVH and GVL may be
mediated by different cells, but more research is needed to
make this determination.  Both class I and class II HLA
antigens have relevance, although matching at the class II
loci (DR, DP, and DQ) may be especially important.
 
In the past, HLA antigens have been defined serologically,
usually by cytotoxicity assays (HLA D, seemingly related to
serologically defined DR, and HLA DP are defined by cellular
interactions, but the procedure is cumbersome and uncommonly
used in practice).  Recent evidence suggests that more
refined biochemical and molecular biological techniques will
discern differences that are not detectable serologically or
are detectable in only limited fashion.  It is possible that
these molecular differences are important to graft (and
patient) survival and to the presence, absence or severity of
GVH disease.  Techniques used in the past have included
isoelectric focussing, restriction fragment length
polymorphism (RFLP) analysis, and direct structural
evaluation using DNA probes, with or without preparation with
the polymerase chain reaction.  It seems likely that HLA
typing using these newer techniques will be more precise,
more reliable, more specific, and even possibly more cost-
effective than the currently available serological
procedures.  The molecular approach to HLA typing is furthest
along in the class II antigens, possibly because serological
reagents have been limited in both quantity and quality.  For
the study of Class I antigens, isoelectric focussing has been
used but analysis using DNA probes is in its infancy.  The
sequence of many class I alleles has yet to be determined.
Class I typing reagents are of good quality and in plentiful
supply, making molecular techniques better suited to
splitting HLA A and B into subtypes, when needed.  It is
probable that the size of the market for reagents to do HLA
typing at the molecular level is not large enough to merit
other than an "orphan" procedure classification.
Nevertheless, careful molecular HLA-typing may be important
for marrow donor-recipient matching to maximize engraftment
and minimize GVH disease.  Such an approach to HLA-typing may
be a sine-qua-non for patients with insufficient peripheral
blood lymphocytes for serological typing.
 
There is a repository of cryopreserved lymphocytes from each
donor-recipient pair transplanted under the National Marrow
Donor Program (NMDP).  This repository will be very useful in
answering the questions posed in the preceding paragraph.
 
Most serological typing reagents have come from caucasians
sensitized to HLA antigens.  Minority groups are under-
represented.  There are some HLA types that are peculiar to
certain racial or ethnic groups;  others are more common in
some such groups than in others.  An important proportion of
some racial groups (e.g., African-Americans) can often be
only incompletely typed because antisera do not
differentiate some of their HLA antigens.  Furthermore, some
DR antigens react similarly in serological tests but show
molecular differences (e.g., DR 11.1 in caucasians and DR
11.2 in African-Americans).  It may be impossible to get good
class II typing for minority-group patients and donors
without using molecular techniques.
 
The NHLBI has assumed responsibility for the
NMDP, which has as a major goal the provision
of carefully HLA-matched, unrelated bone marrow donors for
patients in need of a transplant, but without related donors.
As part of this responsibility, the NHLBI would like to
encourage the application of molecular biological techniques
to the typing of patients and donors for HLA class I and
class II antigens.  It is particularly important to define
various alleles at the molecular level, comparing the
findings with those obtained by serological techniques and
determining the importance to bone marrow transplantation of
the degree and characteristics of molecular matching.  For
appropriate projects and under appropriate circumstances,
cultured cells from donor-recipient pairs (now >315) in the
NMDP repository may be made available to qualified
investigators.  The outcome of the marrow transplant is known
for each of these pairs.
 
The donor registry now contains 148,082 volunteers, and is
increasing at a rate of 5,000-10,000 each month.  Most of
these are HLA class I typed only, and in facilities that do
not detect appropriate splits.  It is important to have
accurate typing to include known splits of "public" antigens.
Furthermore, it is both scientifically and financially
important to perform both class I and II antigen typing for
all donors in the file prospectively.   The next preliminary
goal is to have 250,000 such donors, but that may have to be
modified upward as experience in the frequency distribution
of HLA phenotypes is gained.  When a registry of sufficient
size is developed, present evidence suggests that new donors
will still be needed to replace approximately 10 percent each
year, as they drop out or otherwise become ineligible.  The
limiting factors for increasing the size of the donor file is
HLA typing -- facilities to do the typing in sufficient
quantity and with sufficient quality, as well as funds to
defray the cost.  Applying semi-automated, molecular
techniques in one or more laboratories can overcome these
limiting factors.  Furthermore, DNA-based techniques do not
require fresh blood with viable cells, so that sudden bulges
in donor recruitment can more easily be managed.  To meet the
goals of the NMDP, it will likely be necessary to type at
least 100,000 marrow donors each year.
 
OBJECTIVES AND SCOPE
 
The objective of this initiative is to support the basic and
applied research necessary to bring molecularly-based HLA
class I and II typing to the point where it can be clinically
useful and cost-beneficial for the marrow donor registry or
other purposes.  The aim is to encourage research to develop
the necessary probes and automated or semi-automated
techniques to provide high-quality HLA typing at minimal
cost.
 
MECHANISM OF SUPPORT
 
The support mechanism for this five-year program will be the
traditional, individual research grant.  Although
approximately $1,000,000 (for direct plus indirect costs) for
this program is included in the financial plans for fiscal
year 1991, award of grants pursuant to this Request for
Applications (RFA) is contingent
upon receipt of funds for this purpose.  It is anticipated
that about 4 grants will be awarded under this program.  The
specific number to be funded, however, depends upon the merit
and scope of the applications received and the availability
of funds.  It is anticipated that the range of costs
proposed in responses to this announcement will be
relatively narrow.
 
Upon initiation of this program, DBDR
will sponsor periodic meetings to
encourage exchange of information among investigators with
research interests in this area.  In the preparation of the
budget for the grant application, applicants should request
travel funds for a one-day meeting each year, most likely to
be held in Bethesda, Maryland.  Applicants should also
include a statement in their applications indicating their
willingness to participate in such meetings.
 
Applicants are requested to furnish their own estimates of
the time required to achieve the objectives of the proposed
research project.  However, the maximum award period for this
activity is 5 years.  At the end of the initial award period,
renewal applications may be submitted at the investigator's
discretion for peer review and competition for support as
part of the regular grant program of the NIH.  Although it is
anticipated that support will begin in July 1991, it should
be noted that the first year of any award made in response to
an Institute-solicited program may be for less than the 12-
month recommended period.
 
All current policies and requirements that govern research
grant programs of the National Institutes of Health (NIH) will
apply to grants awarded in connection with this RFA.  Awards
in connection with this announcement will be made to foreign
institutions only for research of very unusual merit, need,
and promise, and in accordance with Public Health Service
policy governing such awards.
 
Women and minority individuals should be included in the
study population; otherwise a clear rationale for their
exclusion must be provided in the application.  Minority
institutions are encouraged to apply, and other institutions
are encouraged to establish collaborative arrangements with
minority institutions.
 
REVIEW PROCEDURES AND CRITERIA
 
Review Method.  All applications submitted in response to
this RFA will be reviewed for scientific and technical merit
by an initial review group, which will be convened by the
Division of Extramural Affairs, NHLBI, solely to review these
applications.  The special ad hoc review group will be
composed of reviewers with special expertise in such areas as
tissue and leukocyte immunology, nucleic acid molecular
biology, transplantation immunology, hematology, and bone
marrow transplantation biology.  Upon receipt, applications
will be reviewed for their responsiveness to the objectives
of this RFA.  If an application is judged unresponsive, the
applicant will be contacted and given an opportunity to
withdraw the application or to have it considered for the
regular grant program of the NIH.
 
If the application submitted in response to this RFA is
substantially similar to a research grant application already
submitted to the NIH for review, but 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 cannot be submitted in response to this
RFA that is essentially identical to one that has already been
reviewed.  This does not preclude the submission of substantial
revisions of applications already reviewed, but such applications
must include an introduction addressing the previous critique.
 
Review Criteria.
 
The factors to be considered in the evaluation of the
scientific merit of each application will be similar to those
used in the review of traditional research project
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; the suitability of the facilities;
and the appropriateness of the requested budget to the work
proposed.  In addition, the review will consider the
likelihood of achieving objectives related to cost-effective
molecular-based HLA typing and of improving the ease with
which minority-group members can be HLA typed.
 
METHOD OF APPLYING
 
Letter of Intent.  Prospective applicants are asked to submit
a one-page letter of intent that includes the identification
of any other participating institutions or investigators.
Such letters are requested for the purpose of obtaining an
indication of the number of applications to be received and,
therefore, the NHLBI does not acknowledge their receipt.  A
letter of intent is not binding, nor is it a necessary
requirement for application.  This letter should be received
no later than September 28, 1990, and should be sent to:
 
Dr. Charles Turbyfill
Division of Extramural Affairs
National Heart, Lung, and Blood Institute
Westwood Building, Room 553A
Bethesda, MD  20892
Telephone:  (301) 496-7351
 
Format for Applications.  Submit applications on form PHS-398
(revised 10/88), the application form for the traditional
research project grant.  This form is available in an
applicant institution's office of sponsored research or from
the Division of Research Grants, NIH, Westwood Building, Room 449,
Bethesda, MD 20892.  Use
the conventional format for research project grant
applications and ensure that the points identified in the
section on "Review Procedures and Criteria" in this RFA are
fulfilled.  To identify the application as a response to this
RFA, check "yes" on item #2 of page 1 of the application and
enter the title "Molecular Biological Techniques for Studying
Class I and II HLA Antigens" and the RFA number HL-90-14-
B.
 
THE RFA LABEL ENCLOSED WITH THE PHS-398 FORM MUST BE AFFIXED
TO THE BOTTOM OF THE FACE PAGE OF THE ORIGINAL COMPLETED
APPLICATION.  FAILURE TO USE THIS LABEL COULD RESULT IN
DELAYED PROCESSING AND REVIEW OF YOUR APPLICATION.
 
Application Procedure.  Send or deliver the completed
application and four (4) signed, complete photocopies
to:
 
Division of Research Grants
Westwood Building, Room 240
National Institutes of Health
Bethesda, Maryland  20892**
 
Send two additional copies of the application to Dr. Charles
Turbyfill at the address listed under Letter of Intent.
 
IT IS IMPORTANT TO SEND THESE TWO COPIES AT THE SAME TIME AS
THE ORIGINAL AND FOUR COPIES ARE SENT TO THE DIVISION OF
RESEARCH GRANTS.  OTHERWISE, THE NHLBI CANNOT GUARANTEE THAT
THE APPLICATION WILL BE REVIEWED IN COMPETITION FOR THIS RFA.
 
Applications must be received by November 29, 1990.  An
application not received by this date will be considered
ineligible.
 
Timetable
 
Letters of Intent:              September 28, 1990
Receipt Date for Applications:  November 29, 1990
Technical Review:               January 1991
Council Review:                 May 1991
Award Date:                     July 1, 1991
 
Inquiries.  Inquiries regarding this announcement may be
directed to the program administrators:
 
Paul R. McCurdy, MD
Division of Blood Diseases and Resources
National Heart, Lung, and Blood Institute
National Institutes of Health
Federal Building, Room 516
Bethesda, Maryland 20892
Telephone:  (301) 496-8387
 
Luiz H. Barbosa, D.V.M.
Division of Blood Diseases and Resources
National Heart, Lung, and Blood Institute
National Institutes of Health
Federal Building, Room 504
Bethesda, Maryland  20892
Telephone:  (301) 496-1537