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PD-1/PD-L1, PD-1/PD-L2, and other co-inhibitory signaling pathways in transplantation
Maria-Luisa del Rio1, Leo Buhler, Carrie Gibbons
1Laboratory of Immunobiology, School of Biotechnology and Institute of Biomedicine, University of Leon, Leon, Spain.
Abstract:
Transplantation of cells, tissues and vascularized solid organs is a successful therapeutic intervention for many end-stage chronic diseases. The combination of co-stimulatory blockade with the delivery of negative signals to T cells through co-inhibitory receptors would provide a robust approach to modulating T-cell receptor signaling and improving alloantigen-specific control of transplant rejection. This approach based on fundamental knowledge of APC/T-cell interactions may complement conventional therapies in the near future to reinforce long-term allograft survival, and permit minimal immunosuppression. The focus of this review was primarily on two major co-inhibitory signaling pathways, namely PD-1/PD-L1/PD-L2 and BTLA/CD160/HVEM/LIGHT that have been thoroughly characterized in murine models of transplantation using genetically modified mice, specific monoclonal antibodies and fusion proteins.
Insights
Combining co-inhibitory signals with co-stimulatory blockade offers a novel strategy to control T-cell responses and improve transplant rejection outcomes. This approach enhances allograft survival with minimal immunosuppression.
Area of Science:
- Immunology
- Transplantation Biology
- Cellular Signaling
Background:
- Organ transplantation is a vital treatment for end-stage organ failure.
- Current immunosuppression strategies carry significant risks and limitations.
- Understanding T-cell regulation is crucial for improving transplant success.
Purpose of the Study:
- To review the potential of combining co-stimulatory blockade with co-inhibitory signals for transplant rejection control.
- To highlight the role of programmed cell death protein 1 (PD-1) and B- and T-lymphocyte attenuator (BTLA) pathways in transplantation.
- To explore how modulating these pathways can enhance long-term allograft survival and reduce immunosuppression.
Main Methods:
- Review of scientific literature focusing on T-cell co-inhibition and co-stimulation.
- Analysis of data from murine models of transplantation.
- Examination of studies utilizing genetically modified mice, monoclonal antibodies, and fusion proteins targeting PD-1 and BTLA pathways.
Main Results:
- Co-inhibitory pathways like PD-1/PD-L1/PD-L2 and BTLA/CD160/HVEM/LIGHT are critical in modulating T-cell responses.
- Targeting these pathways, alongside co-stimulatory blockade, shows promise in controlling alloantigen-specific T-cell activity.
- These strategies have been validated in preclinical murine models.
Conclusions:
- Combining co-stimulatory blockade with co-inhibitory receptor signaling presents a robust strategy for transplant rejection management.
- This approach can lead to improved long-term allograft survival and allow for minimal immunosuppression.
- Further research into these pathways may lead to next-generation transplantation therapies.
