# Regeneration of the Immune System after Radiation Exposure

> **NIH NIH U01** · ALBERT EINSTEIN COLLEGE OF MEDICINE · 2022 · $582,293

## Abstract

Abstract
Radiation-Induced Immune Dysfunction (RIID) is a critical component of both acute and delayed effects of
radiation exposure, which causes a multi-organ failure (MOF) syndrome, operationally divided based upon timing
of clinical manifestations, as acute radiation syndrome (ARS) and delayed effects of acute radiation exposure
(DEARE). The immediate lethality of ARS is caused by bone marrow and intestinal failure, with subsequent
neutropenia, anemia, thrombocytopenia, lymphopenia, and loss of intestinal epithelial barrier, resulting in
bacteremia, septic shock, and systemic inflammatory response. To date, FDA-approved radiation
countermeasures are hematopoietic growth factors, such as, G-CSF, GM-CSF and Romiplostim that promote
myeloid regeneration in the marrow. Ionizing radiation (IR) can cause reversible and irreversible damage to the
immune system. Atomic bomb (A-bomb) survivors from Japan exhibited reduction in T helper cell subsets,
alterations in naïve and memory T and B lymphocyte numbers and function, increased levels of serum pro-
inflammatory cytokines, indicating significant residual injury and impairment of lymphocyte homeostasis in the
lymphoid organs.
We will investigate the immune landscape of regeneration in bone marrow, peripheral lymphoid organs (spleen,
thymus, and peritoneal lymph nodes) and mucosa-associated lymphoid tissue (MALT) of the intestine and lungs,
determine the functionality of antigen presenting cells, and whether IR induces mitochondrial dysfunction, inhibits
macro- and chaperone-mediated autophagy, and accelerates T cell immunosenescence and inflammation
following WBI under aim 1. We will also examine the regeneration of immune effector cells for mitochondrial
dysfunction, inhibition of autophagy, accelerated immunosenescence, T cell exhaustion and inflammation in
lymphocytes from peripheral lymphoid organs in mice exposed to IR and treated with radio-mitigators, TPOm or
Flt3L or G-CSF (as control), 1-day post-WBI in aim 2. Under aim 3 we will develop an immuno-conditioning
regimen to restore functional immune deficit for immunization protocols in radiation survivors, treated with or
without radio-mitigators. We will also examine the effects of metformin and p38/MAPK inhibitor to overcome T
cell immunosenescence as conditioning regimens with immunological outcomes measured by antigen-specific
IgM, IgG and Th1 and Th2 responses.
Relevance. Our proposal will define the functional radio-immunobiology of the regenerative immune system
after WBI in mice. Since the tissue targets of radiation injury are well studied, we can also correlate whether T
cell immunosenescence and dysfunction of myeloid population contributes to DEARE. These studies will provide
a blueprint for developing optimized immuno-conditioning regimens for immunization protocols in radiation
survivors that can be extended to immunocompromised and elderly population.

## Key facts

- **NIH application ID:** 10474871
- **Project number:** 1U01AI170032-01
- **Recipient organization:** ALBERT EINSTEIN COLLEGE OF MEDICINE
- **Principal Investigator:** Chandan Guha
- **Activity code:** U01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $582,293
- **Award type:** 1
- **Project period:** 2022-08-18 → 2027-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10474871

## Citation

> US National Institutes of Health, RePORTER application 10474871, Regeneration of the Immune System after Radiation Exposure (1U01AI170032-01). Retrieved via AI Analytics 2026-05-25 from https://api.ai-analytics.org/grant/nih/10474871. Licensed CC0.

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