# Understanding the unique role endogenous APC subtypes play during the rejection of MAg-mismatched cells

> **NIH NIH R01** · DARTMOUTH COLLEGE · 2020 · $425,145

## Abstract

Project Summary/Abstract
 A major obstacle in organ transplantation is the immunological response against donor tissue grafts.
Both major (MHC) and minor histocompatibility antigens (mAgs) are known to elicit targeted rejection, and
even when a donor's and recipient's MHC antigens are matched, mAgs can elicit graft rejection. In addition,
mismatched mAgs are generated in many other settings, such as during tumorigenesis or induction of DNA
damage induced by ultraviolet radiation. Thus, understanding the mechanisms by which the immune system
recognizes and clears cells expressing mismatches of mAg has broad scientific and translational utility.
 The rejection of mAg-mismatched cells is complex, involving both adaptive (T cells and B cells) and
innate (dendritic cells (DC) and antigen-presenting monocytes) branches of the immune system. To date, it is
poorly understood how endogenous antigen-presenting cells recognize, coordinate and induce an
immunological response against mAg-mismatched cells, particularly in the absence of pathogen-associated
molecular patterns (PAMPs). Preliminary experiments in our laboratory suggest that there is almost no
redundancy in the role individual endogenous APC subtypes play to coordinate the rejection of mAg-
mismatched cells. Multiple APC subtypes play unique roles in mounting an immune response against mAg-
mismatched cells, and blocking any link in the cascade of events should abolish the response against mAg-
mismatched cells. If we can better understand the sequential cellular cascade that leads to mAg-mismatched
cell rejection, then we can design drugs to target specific cell types and signaling pathways to improve the
outcome of transplantation and other adverse diseases.
 What is novel and most striking about the immunological response we propose to investigate is that the
induction of adaptive immunity against mAgs occurs without external stimuli (i.e. PAMPs). Therefore, in Aim 1,
we will investigate the role of B cells and the endogenous molecules they secrete to alert the immune system
to the presence of mismatches of mAg on cells. We hypothesize that the initial molecule that binds and coats
adoptively transferred mAg-mismatched cells are natural IgM antibodies, resulting in the formation of an
immune complex. In Aim 2 we will examine the mechanisms by which a cellular immune complex is acquired
by Irf4+ DCs and/or Ly6C+ monocytes. In addition, we will examine how the acquisition of an immune complex
activates and licenses Irf4+ DCs and/or Ly6C+ monocytes to present mAg in an immunogenic way to CD4+ T
cells. Subsequently, we will investigate how these activated effector mAg-specific CD4+ T cells help license
Batf3+ DCs via CD40 to cross-present cell-associated mAgs and prime cytotoxic CD8+ T cells, which is
ultimately required to complete the process of mAg-mismatched cell rejection. All in all, the accomplishment of
our proposed aims will constitute a significant advance in our in vivo understanding of...

## Key facts

- **NIH application ID:** 9838257
- **Project number:** 5R01HL115334-09
- **Recipient organization:** DARTMOUTH COLLEGE
- **Principal Investigator:** Claudia V Jakubzick
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $425,145
- **Award type:** 5
- **Project period:** 2013-01-04 → 2020-11-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9838257

## Citation

> US National Institutes of Health, RePORTER application 9838257, Understanding the unique role endogenous APC subtypes play during the rejection of MAg-mismatched cells (5R01HL115334-09). Retrieved via AI Analytics 2026-05-27 from https://api.ai-analytics.org/grant/nih/9838257. Licensed CC0.

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