Selective targeting of human alloresponsive CD8+ effector memory T cells based on CD2 expression
D J Lo1, T A Weaver, L Stempora
1Emory Transplant Center, Emory University, Atlanta, GA, USA.
Summary
Costimulation blockade with belatacept is a new transplant therapy. Alefacept targets CD2, controlling T cells resistant to belatacept, suggesting a combined therapy for better transplant outcomes.
Area of Science:
- Immunology
- Transplantation immunology
- T cell biology
Background:
- Costimulation blockade (CoB) using belatacept is an alternative to calcineurin inhibitors in allotransplantation.
- Belatacept may not fully control T cells that downregulate CD28 during differentiation.
- Alefacept, targeting CD2, has shown efficacy against CoB-resistant rejection in primates.
Purpose of the Study:
- To investigate the role of CD2 expression in human alloreactive T cells.
- To determine if alefacept can overcome belatacept resistance in T cells.
- To assess the potential for combining alefacept and belatacept in clinical transplantation.
Main Methods:
- Polychromatic flow cytometry to analyze T cell surface markers (CD2, CD28).
- Assessment of cytokine and cytotoxic molecule expression in T cells.
- In vitro studies evaluating T cell proliferation in response to belatacept and alefacept.
Main Results:
- CD8(+) effector memory T cells express high CD2 and low CD28.
- Alloresponsive CD8(+) CD2(hi) CD28(-) T cells exhibit potent polyfunctional effector capabilities.
- Belatacept partially inhibited T cell proliferation, while alefacept effectively blocked belatacept-resistant proliferation.
Conclusions:
- Highly alloreactive T cells can function independently of CD28/B7 costimulation.
- Elevated CD2 expression on these T cells makes them susceptible to alefacept.
- Combining alefacept and belatacept presents a promising strategy for human renal transplantation.
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