# Project-002

> **NIH AI P01** · UNIVERSITY OF CHICAGO · 2026 · $1,141,324

## Abstract

Project 2 Summary 
 Transplantation tolerance promises to facilitate long-term allograft acceptance while avoiding the need for 
life-long immunosuppression and its associated problems. In the past decade, operational clinical transplantation 
tolerance has been achievable through hematopoietic stem cell transplantation or weaning of conventional 
immunosuppression. However, the vast majority of transplant recipients fail to achieve allograft tolerance, and a 
subset of operationally tolerant transplant recipients eventually experience graft loss. High frequencies of 
memory alloreactive CD4+ or CD8+ T cells have been identified as potent barriers to the successful induction of 
transplantation tolerance. There continues to be an urgent need to identify new strategies for overcoming the 
barrier posed by memory T cells; Project 2 proposes to address this need. We recently showed that memory T 
cells resist infectious tolerance mechanisms, and cannot acquire the cell-intrinsic hypofunctional states attained 
by naïve T cells. Moreover, in sensitized recipients harboring memory T cells directed to just a single donor 
antigen, we reported that the larger repertoire of naïve donor-specific CD4+ Tconv also develops resistance to 
co-stimulation blockade-induced tolerance. We refer to this phenomenon as “linked sensitization” and posit that 
understanding the mechanism underlying this barrier to co-stimulation blockade-induced allograft tolerance is 
not only relevant to recipients with heterologous memory T cells, but also can lead to the identification of new 
targets that synergize with co-stimulation blockade to achieve transplantation tolerance. Aim 1 will focus on 
defining the mechanism of linked sensitization. Our observations that memory T cells are resistant to being 
programmed into cell-intrinsic hypofunctional states identify a gap in knowledge as to whether, and how, memory 
T cells may be programmed to tolerance. To this end, we leveraged the physiological

## Key facts

- **NIH application ID:** 11528790
- **Project number:** 5P01AI097113-14
- **Recipient organization:** UNIVERSITY OF CHICAGO
- **Principal Investigator:** Maria-Luisa  Alegre; Anita S Chong
- **Activity code:** P01 (R01, R21, SBIR, etc.)
- **Funding institute:** AI
- **Fiscal year:** 2026
- **Award amount:** $1,141,324
- **Award type:** 5
- **Project period:** 2012-07-17T00:00:00 → 2028-04-30T00:00:00

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/11528790

## Citation

> US National Institutes of Health, RePORTER application 11528790, Project-002 (5P01AI097113-14). Retrieved via AI Analytics 2026-07-02 from https://api.ai-analytics.org/grant/nih/11528790. Licensed CC0.

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