FTY720 Prevents Anti-CD4 mAb-Induced Tolerance but Cannot Reverse Established Tolerance in a Rat Kidney Transplantation Model

Abstract

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 TM -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 upregulation 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.

Fifty Shades of Transplantation Tolerance: Beyond a Binary Tolerant/Non-Tolerant Paradigm

“…The latter is also resistant to breaking by individual interventions, such as increasing the numbers of naïve alloreactive T cells, or allowing T cells to homeostatically proliferate, or providing additional alloantigen and ischemia-reperfusion inflammation via giving a new transplant, or depleting Tregs [13–15]. Additionally, Schroeder et al, showed that established tolerance induced with anti-CD4 alone was resistant to breakage with FTY720, an intervention that is capable of preventing the induction of tolerance [16]. This observation suggests that recirculation of new immune cells to the graft is not necessary for maintenance of tolerance, but is necessary for its induction.…”

Tracking of TCR-Transgenic T Cells Reveals That Multiple Mechanisms Maintain Cardiac Transplant Tolerance in Mice

“…In addition to infections, manipulations that increase the na€ ıve or memory T cell precursor frequency, or those that directly target mechanisms of peripheral T cell tolerance (i.e. preventing apoptosis, depleting/inhibiting regulatory cells, or blocking signals through the negative regulatory PD-1/PD-L1 [programmed cell death protein 1/programmed death ligand-1] pathway) all result in the inability to induce tolerance (7)(8)(9)(10)(11)(12)(13)(14)(15)(16).…”

Dextran Sulfate Facilitates Anti-CD4 mAb-Induced Long-Term Rat Cardiac Allograft Survival After Prolonged Cold Ischemia

“…It has been reported that the use of FTY720 in combination with RIB 5/2 prevents tolerance induction (45). Therefore, the selection of drugs for synergistic treatment with tolerance induction protocols appears to be a challenge.…”