# Costimulation Blockade-Based Strategies for Tolerance Induction

> **NIH NIH U19** · EMORY UNIVERSITY · 2022 · $665,247

## Abstract

Costimulation blockade represents a new class of immunosuppression with more specific targets
accompanied by less toxicity. Belatacept is the first FDA approved costimulation blockade reagent for use
in kidney transplant recipients. Despite superior renal function, improved cardiovascular risk profile, and
significantly better patient and graft survival at 7 years, the high rates of rejection as well as other logistical
challenges have limited the breadth of its clinical adoption. We have observed similar benefits in renal
function but were surprised by the high rates of rejection we observed when using it outside the context of
a clinical trial, nearly double what was previously reported. It is interesting to note that approximately half of
the patients experienced rejection while the other half did not, provoking the question as to why some
patients are susceptible while others are resistant to costimulation blockade therapy. Our early studies in
mice and non- human primates (NHP) identified costimulation blockade resistant rejection as an important
area for investigation and emphasized the potential benefits of developing a successful tolerance strategy.
One of the most effective methods to promote tolerance in experimental models has been the transient
disruption of the CD28 and CD40 pathways during the introduction of donor antigens. We have evaluated
the next generation of costimulation blockade reagents (domain antibodies targeting CD28 and CD154)
and shown that they are both safe and efficacious. Despite these advances there is still a subset of animals
and patients who reject while on therapy. In comparing these rejecting vs. stable recipients, we have
identified a memory T cell biomarker that correlated with increased risk of costimulation blockade-resistant
rejection in both NHP and humans. We posit that the use of this predictive biomarker may allow us to
identify optimal candidates for costimulation-blockade- based therapies and propose to longitudinally
assess the stability and plasticity of this biomarker and test its predictive power in a prospective fashion in
animals receiving dual costimulation blockade therapy. Further exploration of critical pathways utilized by
costimulation-independent memory T cells and development of next-generation cellular therapies including
mesenchymal stromal cells (MSCs) will provide powerful strategies to mitigate the risk of rejection and
promote tolerance induction in particularly rejection-prone recipients. The development of tolerance
induction protocols based on the immune status of individual recipients will facilitate personalized strategies
for tolerance, to minimize peri- transplant immunosuppression and preserve protective immunity.

## Key facts

- **NIH application ID:** 10609611
- **Project number:** 4U19AI051731-21
- **Recipient organization:** EMORY UNIVERSITY
- **Principal Investigator:** Andrew B Adams
- **Activity code:** U19 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $665,247
- **Award type:** 4C
- **Project period:** 2022-08-01 → 2023-10-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10609611

## Citation

> US National Institutes of Health, RePORTER application 10609611, Costimulation Blockade-Based Strategies for Tolerance Induction (4U19AI051731-21). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10609611. Licensed CC0.

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