Transplant-tolerance induction by CTLA-4Ig in liver-transplanted rats: a lesson for the treatment of autoimmune diseases?

Introduction

The immunology of transplantation is of general interest, because "it offers one of the few negotiable pathways into the central regions of biology" (Medawar, 1957). The holy grail of transplantation immunology is tolerance induction. This might be achieved in the clinic by blocking the T-cell costimulation using CTLA-4Ig, a fusion protein consisting of the extracellular domain of CTLA-4 linked to the constant region of IgG₁. CTLA-4Ig proved to be effective in prolonging the transplant survival in various transplantation models [1] and in the treatment of autoimmune diseases. CTLA-4Ig is currently under investigation in a clinical trial to determine its safety and efficacy for patients suffering from rheumatoid arthritis [2].

Experiment

CTLA-4Ig was administered on days 3 and 4 after rat liver transplantation in a MHC-mismatched donor–recipient combination. We also studied the therapeutic effect of donor-specific splenocyte transfusions on day 4 alone and in combination with CTLA-4Ig on days 3 and 4. We achieved a prolonged transplant acceptance in the animals receiving the combination of cells and CTLA-4Ig, and investigated whether a Th1/Th2 immune deviation might be responsible for this phenomenon.

Methods

A rat liver transplantation model in a high-responder rat strain combination was used. The Th1 cytokines IL-2 and IFN-γ and the Th2 cytokines IL-4 and IL-10 were analysed by RT-PCR.

Results

CTLA-4Ig prolonged the survival of the recipients from 10 days median in the untreated control group to 30 days median. Donor-specific splenocytes alone had no influence on the survival, but the combination of CTLA-4Ig and donor-specific splenocytes resulted in a survival of > 150 days in all animals. A Th1/Th2 immune deviation was not observed in the animals with long-term graft acceptance. The Th1 cytokines IL-2 and IFN-γ and the Th2 cytokines IL-4 and IL-10 were equally expressed in the control group and in the group with prolonged transplant acceptance.

Conclusions

The combination of CTLA-4Ig and donor-specific splenocytes results in a long-term transplant acceptance (> 150 days), which cannot be achieved by CTLA-4Ig or a splenocyte transfusion alone. The Th2 cytokines are not dominant protective in preventing the transplant rejection.