# INDUCTION OF UNRESPONSIVENESS TO ALLOGRAFTS

> **NIH NIH R01** · NEW ENGLAND DEACONESS HOSPITAL · 1993 · $393,373

## Abstract

The use of polyclonal antilymphocyte serum (ALS) treatment and donor
specific bone marrow infusion (BM) has been extremely effective in
inducing specific tolerance to tissue allografts in rodents.  This
model has also been successful in inducing tolerance to immediately
vascularized whole organ renal allografts in dogs, non-human primates
and possibly man.  The basic premise of this proposal is that multiple
tolerance mechanisms are involved which appear sequentially and are
interrelated as tolerance evolves and is stabilized.

FACS analysis will be used to identify the sequential appearance of
peripheral and central (thymic) lymphoid chimerism.  Limiting dilution
analysis (LDA) will be performed serially to identify the frequency of
precursor cytotoxic lymphocytes and FACS analysis will be done to
identify recipient T cells with TcR specific for the donor.  These
studies will provide evidence for clonal deletion or reduction as a
mechanism in tolerance.  Standard suppressor cell adoptive transfer
assays will be done serially to identify active suppressor cell
mechanisms.  Depletion experiments using specific monoclonal
antibodies prior to adoptive transfer will be employed to identify the
source and phenotype of the putative suppressor cells.  Serial
lymphokine production in vitro by lymphocytes from tolerant animals
(IL-2, IL-4, IL-10, IFN-g) will be performed to determine if tolerance
is associated with altered lymphokine production at any time.
Parallel studies in tolerant recipients will determine the total T
helper cell, Th1 and Th2 helper cell frequencies by modified LDA
analysis to see if tolerance is associated with differentiated T
helper cell activation.  Related studies will seek to modify tolerance
by appropriately timed exogenous lymphokine (IL-2, IFN-g)
administration based on deficiencies of lymphokine production
identified in in vitro studies.  Since the active cells in BM that
induce tolerance are of stem cell lineage, experiments will be
performed to attempt to augment BM tolerogenicity by treatment with
lymphokines in vivo and in vitro (IL-3, GM-CSF) known to modify stem
cells.  Since rapamycin markedly augments the tolerance induced by ALS
and BM, experiments will be done to examine if and how the
mechanism(s) associated with tolerance in ALS, BM mice are altered in
ALS, BM mice given rapamycin.

The focus of this grant proposal is elucidation of the mechanisms
involved in the ALS, BM tolerance model.  Detailed understanding of
the mechanism(s) should provide important information to permit
successful application of this tolerance protocol to clinical
transplantation.

## Key facts

- **NIH application ID:** 3125788
- **Project number:** 2R01AI014551-16A2
- **Recipient organization:** NEW ENGLAND DEACONESS HOSPITAL
- **Principal Investigator:** Anthony P Monaco
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 1993
- **Award amount:** $393,373
- **Award type:** 2
- **Project period:** 1978-05-01 → 1996-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/3125788

## Citation

> US National Institutes of Health, RePORTER application 3125788, INDUCTION OF UNRESPONSIVENESS TO ALLOGRAFTS (2R01AI014551-16A2). Retrieved via MORVS 2026-10-25 from https://api.morvs.ai/grant/nih/3125788. Licensed CC0.

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