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Published on: May 2, 2013
Ex Vivo Costimulatory Blockade to Generate Regulatory T Cells From Patients Awaiting Kidney Transplantation
E C Guinan1,2, G A Cole3, W H Wylie3
1Department of Radiation Oncology, Dana-Farber Cancer Institute, Boston, MA.
Abstract:
Short-term outcomes of kidney transplantation have improved dramatically, but chronic rejection and regimen-related toxicity continue to compromise overall patient outcomes. Development of regulatory T cells (Tregs) as a means to decrease alloresponsiveness and limit the need for pharmacologic immunosuppression is an active area of preclinical and clinical investigation. Nevertheless, the immunomodulatory effects of end-stage renal disease on the efficacy of various strategies to generate and expand recipient Tregs for kidney transplantation are incompletely characterized. In this study, we show that Tregs can be successfully generated from either freshly isolated or previously cryopreserved uremic recipient (responder) and healthy donor (stimulator) peripheral blood mononuclear cells using the strategy of ex vivo costimulatory blockade with belatacept during mixed lymphocyte culture. Moreover, these Tregs maintain a CD3(+) CD4(+) CD25(+) CD127(lo) surface phenotype, high levels of intracellular FOXP3 and significant demethylation of the FOXP3 Treg-specific demethylation region on allorestimulation with donor stimulator cells. These data support evaluation of this simple, brief Treg production strategy in clinical trials of mismatched kidney transplantation.
Insights
Generating regulatory T cells (Tregs) from kidney transplant patients is feasible using belatacept. This method can potentially reduce immune rejection and reliance on immunosuppressive drugs.
Area of Science:
- Immunology
- Transplantation Medicine
- Cell Therapy
Background:
- Kidney transplant outcomes are limited by chronic rejection and drug toxicity.
- Regulatory T cells (Tregs) show promise for reducing immune responses and immunosuppression needs.
- The impact of end-stage renal disease on Treg generation strategies is not fully understood.
Purpose of the Study:
- To investigate the efficacy of generating recipient Tregs from uremic patients for kidney transplantation.
- To assess the feasibility of using ex vivo costimulatory blockade with belatacept for Treg expansion.
Main Methods:
- Peripheral blood mononuclear cells from uremic recipients and healthy donors were used.
- Ex vivo costimulatory blockade with belatacept was employed during mixed lymphocyte culture.
- Treg phenotype, FOXP3 expression, and demethylation status were analyzed post-allorestimulation.
Main Results:
- Successful generation of Tregs from both fresh and cryopreserved uremic patient samples.
- Generated Tregs exhibited a stable CD3(+) CD4(+) CD25(+) CD127(lo) phenotype.
- High intracellular FOXP3 levels and demethylation of the FOXP3 locus were observed, confirming Treg identity.
Conclusions:
- A simple and brief strategy for producing Tregs from kidney transplant recipients was established.
- This Treg generation method shows potential for clinical application in mismatched kidney transplantation.
- Further evaluation in clinical trials is warranted to validate this approach.
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