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Translating costimulation blockade to the clinic: lessons learned from three pathways
Mandy L Ford1, Christian P Larsen
1Department of Surgery, Emory Transplant Center, Emory University, Atlanta, GA 30322, USA.
Summary:
As the recognition that costimulatory signals are critical for optimal T-cell activation, proliferation, and differentiation, there has been an explosion in the study of costimulatory molecules and their roles in enhancing anti-donor T-cell responses following transplantation. Here, we focus on the bench-to-beside translation of blocking agents designed to target three critical costimulatory pathways: the CD28/CD80/CD86 pathway, the CD154/CD40 pathway, and the lymphocyte function associated antigen-1/intercellular adhesion molecule pathway. While blockade of each of these pathways proved promising in inhibiting donor-reactive T-cell responses and promoting long-term graft survival in murine models of transplantation, the progression of development of therapeutic agents to block these pathways has each taken a slightly different course. Both logistical and biological pitfalls have accompanied the translation of blockers of all three pathways into clinically applicable therapies, and the development of costimulatory blockade as a substitute for current standard-of-care calcineurin inhibitors has by no means reached completion. Collaboration between both the basic and clinical arenas will further propel the development of costimulation blockers currently in the pipeline, as well as of novel methods to target these critical pathways during transplantation.
Insights
Blocking costimulatory pathways like CD28/CD80/CD86 shows promise in transplantation by inhibiting T-cell responses and improving graft survival. Further research and collaboration are needed for clinical application.
Area of Science:
- Immunology
- Transplantation Biology
- Drug Development
Background:
- Costimulatory signals are crucial for T-cell activation, proliferation, and differentiation.
- Understanding costimulatory molecules is key to managing anti-donor T-cell responses in transplantation.
Purpose of the Study:
- To review the bench-to-bedside translation of blocking agents targeting three critical costimulatory pathways.
- To assess the progress and challenges in developing these agents for clinical use.
Main Methods:
- Focus on blocking agents for the CD28/CD80/CD86, CD154/CD40, and LFA-1/ICAM pathways.
- Evaluation of preclinical (murine models) and clinical development stages.
Main Results:
- Blockade of these pathways demonstrated potential in inhibiting donor-reactive T-cells and promoting graft survival in murine models.
- Developmental trajectories for agents targeting each pathway have varied, with distinct logistical and biological challenges.
Conclusions:
- Costimulatory blockade shows promise but has not yet replaced standard calcineurin inhibitors.
- Continued collaboration between basic science and clinical research is essential for advancing these therapies.
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