FTY720 Prevents Anti-CD4 mAb-Induced Tolerance but Cannot Reverse Established Tolerance in a Rat Kidney Transplantation Model
Article first published online: 2 APR 2004
American Journal of Transplantation
Volume 4, Issue 6, pages 863–871, June 2004
How to Cite
Schroeder, G., Risch, K., Kotsch, K., Siepert, A., Brock, J., Nickel, P., Reinked, P., Ritter, T., Volk, H.-D. and Lehmann, M. (2004), FTY720 Prevents Anti-CD4 mAb-Induced Tolerance but Cannot Reverse Established Tolerance in a Rat Kidney Transplantation Model. American Journal of Transplantation, 4: 863–871. doi: 10.1111/j.1600-6143.2004.00442.x
- Issue published online: 2 APR 2004
- Article first published online: 2 APR 2004
- Received 20 August 2003, revised and accepted for publication 6 February 2004
- Anti CD4 mAb;
FTY720 is highly effective in various models of transplantation and autoimmunity. In order to find drugs that act synergistically with a tolerance-inducing nondepleting anti-CD4 mAb we studied this combination in a strong DA to LEW kidney transplantation model. Rats were treated with 0.3 mg/kg of FTY720 for 14 days and anti-CD4 mAb RIB5/2, alone or in combination. After kidney transplantation serum creatinine and blood lymphocyte counts were monitored. Immunohistology, ELISPOT and TaqMan™-PCR analysis of biopsies were performed.
Short-term application of RIB5/2 but not FTY720 induced long-term survival of kidney transplants. Moreover, the combination of FTY720 + RIB5/2 prevented tolerance induction. In the combination group serum creatinine levels increased 1 week after cessation of therapy and all rats died from uremia within 72 days. Intragraft immunohistology, ELISPOT and real-time RT-PCR analysis at day 21 demonstrated an enhanced T-cell infiltration and activation but a diminished up-regulation of protective genes in the grafts from recipients receiving the combination therapy. In contrast, delayed application of FTY720 to RIB5/2-treated rats did not interact with RIB5/2-induced tolerance.
In summary, FTY720 is powerful in preventing intragraft infiltration by naive T cells but this might also affect the early development of graft-protecting regulatory T cells and tolerance induction.