# Epigenetic Regulation of Regulatory B Cell Cytokine Expression and Allograft Rejection

> **NIH NIH K08** · UNIVERSITY OF PITTSBURGH AT PITTSBURGH · 2022 · $186,133

## Abstract

PROJECT SUMMARY/ABSTRACT
Despite remarkable short-term outcomes, the rate of late renal allograft loss has not improved. This is
increasingly attributed to the cumulative effects of ongoing subtle immunological injury that often remains
undetected. Clinical parameters and even surveillance biopsies have limited predictive value, underscoring the
need for new predictive biomarkers. Dr. Cherukuri showed that: (i) Human Breg activity is best characterized by
the ratio of IL-10/TNFα expression by immature T1 transitional B cells (T1Bs); and (ii) This T1B IL-10/TNFα ratio
3 mos post-transplant, predicts subsequent acute rejection (AR), allograft fibrosis, decreased eGFR and graft
survival. Furthermore, assessment of T1B IL-10/TNFα ratio prior to transplantation showed that in ~75% of
patients, the cytokine ratio remains stable after transplantation and predicts their risk for AR and subsequent
outcomes (pre-determined). In contrast, in ~25% of patients, the cytokine ratio shifts from high to low or from low
to high, and their risk for subsequent outcomes tracks with the direction of the shift. The mechanisms that
regulate stable vs. switchable T1B cytokine expression are unknown. Understanding such mechanisms will allow
us to accurately risk-stratify patients prior to transplantation and elucidate key regulatory mechanisms that
contribute to an individual patient’s underlying immunological reactivity. We hypothesize that transcriptional
regulation by genetic or epigenetic mechanisms dictate the stability of the T1B cytokine ratio, Breg activity, and
determine a patient’s post-transplant clinical course. This hypothesis will be tested by examining the genetic and
epigenetic underpinnings of stable vs. switchable T1B cytokine expression, and by determining whether clinical
characteristics correlate with these changes. These Aims will allow Dr. Cherukuri to gain expertise in: (i) state of
the art advanced genomic and epigenetic analysis approaches (e.g., ATACseq, bisulfite sequencing, RNAseq),
(ii) bioinformatics, and (iii) traditional statistical modelling, and unsupervised machine learning approaches; in
addition to honing standard lab techniques. These new indispensable approaches for basic and translational
research will facilitate his transition to a career performing meaningful independent research. These skills will be
developed under the guidance of a team of mentors, advisors, and collaborators at the Univ. of Pittsburgh. Dr.
David Rothstein (1° mentor) is an established physician-scientist with expertise in transplant immunology,
tolerance, and Bregs, as well as biomarker research. Dr. Harinder Singh (co-mentor), an internationally
recognized scientist with expertise in genetic and epigenetic regulation of immune responses, directs the Univ.
of Pittsburgh Center for Systems Immunology. Both mentors have excellent training track records. An advisory
committee of accomplished investigators with expertise ranging from fundamental transplant immuno...

## Key facts

- **NIH application ID:** 10349822
- **Project number:** 1K08AI166021-01
- **Recipient organization:** UNIVERSITY OF PITTSBURGH AT PITTSBURGH
- **Principal Investigator:** Aravind Cherukuri
- **Activity code:** K08 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $186,133
- **Award type:** 1
- **Project period:** 2021-12-17 → 2026-11-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10349822

## Citation

> US National Institutes of Health, RePORTER application 10349822, Epigenetic Regulation of Regulatory B Cell Cytokine Expression and Allograft Rejection (1K08AI166021-01). Retrieved via AI Analytics 2026-05-27 from https://api.ai-analytics.org/grant/nih/10349822. Licensed CC0.

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