# Selective induction of alloantigen-specific humoral tolerance by MHC-Fc fusion proteins

> **NIH NIH R21** · WASHINGTON UNIVERSITY · 2022 · $236,250

## Abstract

PROJECT SUMMARY/ABSTRACT
Alloimmunization is the physiological response to allogeneic antigens encountered by the host during pregnancy,
blood transfusion, or transplantation. B cell-derived alloantibodies are generated in this response which do not
contribute to infection control but instead constitute a barrier to life-saving blood transfusion or transplantation.
The most prominent allogeneic humoral barriers are MHC class I human leukocyte antigens (HLA) due to their
strong immunogenicity and broad tissue expression. Donor-specific antibodies to these antigens are leading
causes of antibody-mediated graft rejection and ineffective platelet transfusion. To target HLA-specific antibody-
producing B cells, we have engineered MHC-Fc fusion proteins by linking an HLA class I antigen with the Fc
portion of an antibody molecule. Our preliminary data show that such HLA class I-Fc fusion proteins potently kill
B cell hybridomas with cognate specificities. This effect occurs in an antigen-specific and Fc-dependent manner
in vitro and in vivo. Here, we will extend our findings to examine these lead biologics in pre-clinical settings to
demonstrate their applicability. We hypothesize that MHC-Fc treatment can modify antibody-mediated disease
processes and attenuate alloimmunization to specific MHC class I antigens. We will test this central hypothesis
in three aims. In Aim 1, we will evaluate the efficacy and specificity of MHC-Fc treatment in a platelet
refractoriness model. In Aim 2, we will test the feasibility of desensitization by MHC-Fc treatment in a skin
transplant model. In Aim 3, we will test whether MHC-Fc treatment can induce antigen-specific humoral
suppression in a murine alloimmunization model involving bone fide polyclonal B cells producing anti-MHC class
I antibodies. Our proposed work allows critical evaluation of MHC-Fc prototypes in models that either mimic the
settings of their anticipated clinical applications (Aims 1 and 2) or offer a physiological source of B cells as the
therapeutic target (Aim 3). The results from these experiments will open a novel avenue of research in precision
medicine for the selective induction of antigen-specific humoral tolerance.

## Key facts

- **NIH application ID:** 10432434
- **Project number:** 1R21AI168706-01
- **Recipient organization:** WASHINGTON UNIVERSITY
- **Principal Investigator:** Brian Todd Edelson
- **Activity code:** R21 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $236,250
- **Award type:** 1
- **Project period:** 2022-04-21 → 2024-03-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10432434

## Citation

> US National Institutes of Health, RePORTER application 10432434, Selective induction of alloantigen-specific humoral tolerance by MHC-Fc fusion proteins (1R21AI168706-01). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10432434. Licensed CC0.

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