# Mechanisms of Immune Dysfunction and Morbid Outcome in Response to Shock/Sepsis

> **NIH NIH R35** · RHODE ISLAND HOSPITAL · 2020 · $684,885

## Abstract

   
DESCRIPTION (provided by applicant): While through efforts like the Surviving Sepsis Campaign, ARDSNet and others, supportive therapies have improved survival of the critically injured and/or septic patient, nonetheless, a substantial number still develop this morbid syndrome and die. Unfortunately, as no true medicinal/ molecular therapeutic agent is presently available to treat the developing immune/ organ dysfunction in these individuals or diagnose/ prognose their trajectory, the need remains to further clarify the complex pathobiology of traumatic shock and/or sepsis so as to identify such agents. In this regard, we have recently uncovered a novel role for a family of cell-associated co-inhibitory receptors, Programmed Cell Death Receptor-1 [PD-1] and B-/T-Lymphocyte Attenuator [BTLA] and their respective ligands, popularly referred to as checkpoint proteins. What our data and information developing in the field tell us is that a number of these receptors may have far more diverse cell/organ targets than those of us historically appreciated. While checkpoint protein expression on CD4/CD8 lymphoid cells has a role in these dysfunctional septic processes, one of the novel observations we have made is that they appear to have unanticipated effects on phagocyte as well as `innate regulatory lymphoid cell' functions that also seems to contribute to the increased susceptibility/ immune suppression in the critically ill injured and/or septic patient/ animal. With this in mind, e propose to examine the following general hypothesis in this MIRA: that the classic co-inhibitory receptor(s), PD-1, BTLA and/or their ligands, play a novel role(s) in regulating the development of shock/septic immune/ organ dysfunction via novel myeloid cell and/or select regulatory lymphoid subset interactions with other immune or non-immune cells present in a given tissue. In the 1st sub-project area we will determine how the select expression of PD-1 or BTLA, on myeloid as opposed to lymphoid cells alters the development of morbid events associated with sepsis; then, how the expression of ligands for these co-inhibitory molecules, on leukocytes and/or endothelial/ epithelial cells, contribute to the onset of septic liver, intestine and/or kidey dysfunction. In our 2nd sub-project area, we will utilize a novel murine model of indirect-acute lung injury (iALI)(dual insults of hemorrhage shock followed by CLP) to ask how checkpoint protein expression not only effect the patho-mechanisms driving the development of iALI, but how are these co-inhibitors altering cell `priming'/'innate immune memory'/function. Finally, (3rd)
since the neonate possesses a unique/naïve immune system and is more susceptible to morbid response in the face of infectious challenge; we ask if the expression of members of the PD-1 family and/or their ligands not only have a comparative impact on the response to septic insult, but how it might be mediated? To do this we will interrogate these 3 cog...

## Key facts

- **NIH application ID:** 9916789
- **Project number:** 5R35GM118097-05
- **Recipient organization:** RHODE ISLAND HOSPITAL
- **Principal Investigator:** Alfred Ayala
- **Activity code:** R35 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $684,885
- **Award type:** 5
- **Project period:** 2016-05-01 → 2021-04-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9916789

## Citation

> US National Institutes of Health, RePORTER application 9916789, Mechanisms of Immune Dysfunction and Morbid Outcome in Response to Shock/Sepsis (5R35GM118097-05). Retrieved via AI Analytics 2026-06-01 from https://api.ai-analytics.org/grant/nih/9916789. Licensed CC0.

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