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Published on: May 2, 2013
T-cell co-stimulatory blockade in kidney transplantation: back to the bench
Leonardo V Riella1, Mohamed H Sayegh1
1Transplantation Research Center, Department of Medicine, Renal Division, Brigham and Women's Hospital, Children's Hospital Boston, Harvard Medical School , Boston, Massachusetts, USA.
Abstract:
It is believed that blocking positive T-cell co-stimulatory pathways should lead to long-term graft acceptance. Despite the exciting initial achievements in experimental animal models, targeting co-stimulatory pathways has shown to be much more complex in the clinic. In addition to multiple binding partners, some co-stimulatory interactions have been found to be inhibitory in nature, whereas others were demonstrated to be important in the development of regulatory T cells. Moreover, memory T cells have been shown to be resistant to co-stimulation blockade. Herein we focus on the B7:CD28 pathway and describe the evolution of targeting this pathway with cytotoxic T-lymphocyte antigen-4-Ig from bench to clinic. We also attempt to address possible causes for the unexpected high rejection rate observed in the phase III clinical trials with belatacept, using experimental data obtained from basic science research.
Insights
Blocking T-cell co-stimulatory pathways aims for graft acceptance. However, targeting these pathways, like the B7:CD28 interaction, proved complex in clinics, leading to unexpected rejection rates.
Area of Science:
- Immunology
- Transplantation immunology
Background:
- Blocking T-cell co-stimulatory pathways is a strategy for achieving long-term graft acceptance.
- Initial success in animal models contrasts with clinical complexity.
- Co-stimulatory interactions can be inhibitory or crucial for regulatory T cells, and memory T cells resist blockade.
Purpose of the Study:
- To review the development of targeting the B7:CD28 pathway using cytotoxic T-lymphocyte antigen-4-Ig (CTLA4-Ig).
- To explore reasons for high rejection rates in belatacept clinical trials.
Main Methods:
- Focus on the B7:CD28 pathway and CTLA4-Ig.
- Review of experimental data and clinical trial outcomes.
Main Results:
- Targeting co-stimulatory pathways is more complex than anticipated.
- Unexpectedly high rejection rates were observed in Phase III belatacept trials.
Conclusions:
- The clinical application of co-stimulatory pathway blockade requires further understanding.
- Basic science research may elucidate the causes of clinical trial failures.
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