# ROLE OF MHC GENES IN IMMUNREGULATION

> **NIH NIH R01** · JEWISH HOSPITAL OF SAINT LOUIS · 1991 · $180,385

## Abstract

Clonal deletion in the thymus is the mechanism by which T cells
recognizing autologous autologous MHC class II antigens, Mls antigens,
and the male H-Y antigen are regulated. However, our studies of
transgenic mice expressing physiological levels of human insulin
indicate that tolerance is not maintained by clonal deletion.  These
observations support the idea that additional mechanisms operate in the
peripheral immune system to maintain unresponsiveness of autoreactive T
cells not deleted in the thymus.

Using transgenic mice expressing the human insulin gene, we will dissect
the mechanisms that maintain peripheral tolerance.  To this end, we will
determine: 1) whether insulin-specific Th cells are anergic in
transgenic mice; 2) the role of Ts cells in tolerance expressed by
transgenic mice; 3) whether human insulin-specific CTL can be stimulated
in transgenic recipients of nontransgenic T cells; and, 4) if there is
evidence for clonal deletion of high avidity T cells in transgenic mice.

The second goal of this project is to determine why clonal deletion in
the thymus is not effective for circulating autoantigens such as
insulin.  We hypothesize that clonal deletion of T cells in the thymus
is antigen dose-dependent and that the concentration of insulin which
reaches the thymus in these transgenic mice is insufficient to cause
clonal deletion.  A prediction of this hypothesis is that increasing the
levels of insulin in the circulation will result in clonal deletion of
human insulin-specific T cells.  This will be assessed using transgenic
mice expressing human insulin under the regulation of the
metallothionein promoter or the I-E alpha promoter.

The lessons learned from these studies may provide new approaches to the
treatment of autoimmune diseases.  Thus, our studies will be extended to
an immunological disease model of Experimental Allergic
Encephalomyelitis (EAE).  This system will be used to address the
circumstances in which peripheral mechanisms of maintaining
self-tolerance fail and whether regulation can be re-instated once the
disease occurs.

These model systems are particularly relevant for the understanding of
autoimune diseases in man in which there is evidence that auto-reactive
T cells, present in the peripheral immune system, can escape from the
normal regulatory mechanisms.

Accumulating evidence suggests that autoimmunity may be involved in the
pathogenesis of AIDS.  Thus, our studies may be relevant toward
understanding the immune dysfunction operating in AIDS and lead to the
designing of therapeutic approaches for its treatment.

## Key facts

- **NIH application ID:** 3125591
- **Project number:** 2R01AI013987-14
- **Recipient organization:** JEWISH HOSPITAL OF SAINT LOUIS
- **Principal Investigator:** JUDITH A KAPP
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 1991
- **Award amount:** $180,385
- **Award type:** 2
- **Project period:** 1977-04-01 → 1993-11-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/3125591

## Citation

> US National Institutes of Health, RePORTER application 3125591, ROLE OF MHC GENES IN IMMUNREGULATION (2R01AI013987-14). Retrieved via MORVS 2026-10-25 from https://api.morvs.ai/grant/nih/3125591. Licensed CC0.

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