Guiding postablative lymphocyte reconstitution as a route toward transplantation tolerance

Area of Science:

• Immunology
• Transplantation Science

Background:

• Anti-lymphocyte-depleting antibodies are used for induction therapy in transplantation to reduce long-term immunosuppression.
• Lymphocyte reconstitution, driven by IL-7, can lead to rejection-capable immune cell replenishment, necessitating ongoing immunosuppression.

Purpose of the Study:

• To investigate controlling lymphocyte reconstitution post-T cell depletion to favor tolerance.
• To assess the efficacy of combining anti-IL-7 receptor blockade with rapamycin in murine transplant models.

Main Methods:

• Utilized MHC mismatched skin grafting in murine models.
• Administered a short course of anti-IL-7 receptor blocking antibody post-T cell depletion.
• Combined antibody treatment with the mTOR inhibitor rapamycin.

Main Results:

• The combination therapy significantly delayed graft rejection in one mouse strain and induced tolerance in another.
• Treatment delayed T cell reconstitution and transiently increased regulatory T cells (Tregs) over effector cells.
• Tolerance induction was dependent on TGF-ß, suggesting a role for induced Tregs.

Conclusions:

• Guiding early lymphocyte reconstitution after lympholytic induction is feasible.
• Combination therapy of anti-IL-7R blockade and rapamycin offers a strategy to promote endogenous regulatory mechanisms for improved transplant outcomes.