# Antibody Mediated Immune Regulation

> **NIH NIH P01** · UNIVERSITY OF VIRGINIA · 2020 · $534,598

## Abstract

Project Summary
Antibodies are an essential component of adaptive immunity, providing protection from microbial infection.
However, antibodies can also contribute to disease in the context of autoantibodies and alloantibodies.
Although often considered an endpoint of humoral immunity, it has long been appreciated that antibodies can
also modulate the development of adaptive immune responses in an antigen specific fashion and as a function
of the antigens they recognize. This general phenomenon has been named antibody mediated immune
suppression (AMIS), and has been observed in a wide variety of settings, including immunity to microbial
pathogens, vaccination, transplantation and transfusion. Perhaps the most well known case of AMIS in
humans is the administration of anti-RhD as a therapeutic to prophylax against alloimmunization during
pregnancy and/or delivery, which has been a widely successful approach to decrease hemolytic disease of the
fetus and newborn. Indeed, anti-RhD remains one of the only antigen specific immune therapies, allowing
prevention of immunization to a specific target without general immunosuppression. Thus, the practical
potential of harnessing AMIS for the treatment of human disease is well established. However, despite the
success of anti-RhD, the mechanism of immune suppression remains poorly understood. Moreover, several
studies have reported that anti-RhD paradoxically enhances alloimmunization in some settings, underscoring
our poor understanding of anti-RhD mechanisms of action. Lack of mechanistic understanding has also
hampered attempts to make monoclonal anti-RhD, with some monoclonals suppressing immunity whereas
others enhance. The current application makes use of an innovative preclinical mouse model of
alloimmunization to RBCs to test a series of distinct mechanistic hypotheses regarding AMIS effects, under the
central hypothesis that the IgG subtype of an antibody is a key factor in its ability to regulate immunity. Indeed,
preliminary data demonstrates that IgG subtype determines if an antibody is immune suppressing or immune
enhancing. The proposal uses a combination of novel tools and murine strains, as well as steps to humanize
the murine model. In this context, 3 specific aims are proposed. Specific aim 1: Mechanisms by which IgG2a
anti-RBC antibodies enhance alloimmunization to RBCs. Specific aim 2: Mechanisms by which IgG1 anti-
RBC antibodies suppresses humoral alloimmunization to RBCs. Specific Aim 3: Testing effects and
mechanisms of anti-RBC antibodies on alloimmunization in a humanized mouse model. The long-term goals of
this project are to generate novel mechanistic understanding that will provide the conceptual basis for future
human trials to refine monoclonal anti-RhD, to provide a basis for how AMIS like effects can be applied to other
new therapeutics in different areas, and to generate a basic understanding of how antibodies regulate humoral
immunity in general. Such knowledge is relevant ...

## Key facts

- **NIH application ID:** 10018090
- **Project number:** 5P01HL132819-04
- **Recipient organization:** UNIVERSITY OF VIRGINIA
- **Principal Investigator:** JAMES C. ZIMRING
- **Activity code:** P01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $534,598
- **Award type:** 5
- **Project period:** — → —

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10018090

## Citation

> US National Institutes of Health, RePORTER application 10018090, Antibody Mediated Immune Regulation (5P01HL132819-04). Retrieved via AI Analytics 2026-05-25 from https://api.ai-analytics.org/grant/nih/10018090. Licensed CC0.

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