# PI3K-gamma regulates T cell mediated alloimmunity

> **NIH NIH R01** · BRIGHAM AND WOMEN'S HOSPITAL · 2021 · $392,516

## Abstract

Abstract
Though immunosuppressive agents (ISA) used to prevent rejection have improved over time, they are still
unable to consistently eliminate acute and chronic rejection and they have been implicated in the pathogenesis
of organ failure (i.e., calcineurin inhibitor toxicity). One of the main issues with traditional ISA is that they inhibit
the regulatory pathways in transplantation as well. Therefore, one of the highest unmet needs in
transplantation is to identify novel immunomodulatory strategies which selectively inhibit the pathogenic
alloreactive immune cells but spare regulatory humoral and cellular pathways such as T regulatory cells
(Tregs). Phosphoinositide-3 kinases (PI3K) are lipid kinases that generate critically important messengers for
immune cell function. Among the various subclasses of PI3K, PI3Kγ has received much attention for its
restricted expression in leukocytes and regulatory role in immune cells and inflammation. Nevertheless, the
importance of targeting PI3Kγ signaling pathways in transplantation remains unexplored.
We have generated a substantial amount of data indicating that PI3Kγ inhibition markedly reduces acute heart
transplant rejection. Notably, there was marked synergism between PI3Kγ inhibition and low dose CTLA4-Ig
which resulted in indefinite prolongation of heart allograft survival. Mechanistically, PI3Kγ inhibition resulted in
selective suppression of T effector cells (Teff) while augmenting Tregs. Our mechanistic data also indicate that
PI3Kγ inhibition activates genes known to promote FOXP3 promoter. PI3Kγ inhibition markedly reduced the
production of inflammatory cytokines which induce alloimmunity. Our overall objective is to decipher the
relative contribution of the PI3Kγ subclass in T cell-dependent alloimmunity and use the new information to
support the discovery of therapeutics that have high potential to enhance immunoregulation in alloimmunity.
We hypothesize that by tipping the balance of Teff/Tregs toward Tregs, PI3Kγ inhibition effectively
suppresses transplant rejection. In Aim 1, we will examine the role of pharmacological inhibition of PI3Kγ in
suppressing both acute and chronic rejection. In Aim 2, we will examine the mechanisms by which PI3Kγ
inhibition suppresses alloimmune responses. We will also study the impact of PI3Kγ inhibition on alloantigen
specific Tregs. In Aim 3, we will study the synergism of inhibiting both the PI3Kγ and B7-CD28 pathways in
tolerance induction. Alloimmune responses are critically determined by the balance of Teff and Tregs.
Identifying novel regulatory pathways which control this balance has a significant impact on the design of future
immunomodulatory therapies in transplantation. These studies will provide critical information on the role of
PI3Kγ in controlling the balance of Teff/Tregs. These data can serve as a basis for future PI3Kγ-based
therapies for transplantation.

## Key facts

- **NIH application ID:** 10147139
- **Project number:** 5R01HL141815-04
- **Recipient organization:** BRIGHAM AND WOMEN'S HOSPITAL
- **Principal Investigator:** Reza Abdi
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $392,516
- **Award type:** 5
- **Project period:** 2018-07-01 → 2022-04-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10147139

## Citation

> US National Institutes of Health, RePORTER application 10147139, PI3K-gamma regulates T cell mediated alloimmunity (5R01HL141815-04). Retrieved via AI Analytics 2026-05-26 from https://api.ai-analytics.org/grant/nih/10147139. Licensed CC0.

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