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In Vitro and In Vivo Assessment of T, B and Myeloid Cells Suppressive Activity and Humoral Responses from Transplant Recipients
Published on: August 12, 2017
FTY720 prevents anti-CD4 mAb-induced tolerance but cannot reverse established tolerance in a rat kidney
Grit Schroeder1, Kirsten Risch, Katja Kotsch
1Institute of Medical Biochemistry and Molecular Biology, University of Rostock, Germany. grit.schroeder@med.uni-rostock.de
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 trade mark -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.
Insights
FTY720 combined with anti-CD4 mAb hindered kidney transplant tolerance by increasing T-cell activation and graft damage. Delayed FTY720 application did not affect tolerance, suggesting timing is crucial for synergistic immunosuppression.
Area of Science:
- Immunology
- Transplantation Biology
- Pharmacology
Background:
- FTY720 (fingolimod) is known for its efficacy in transplantation and autoimmune disease models.
- Non-depleting anti-CD4 monoclonal antibodies (mAbs) are explored for inducing transplant tolerance.
- Investigating synergistic drug combinations is vital for improving transplant outcomes.
Purpose of the Study:
- To evaluate the synergistic effects of FTY720 and anti-CD4 mAb RIB5/2 in a kidney transplantation model.
- To determine if this combination enhances or inhibits tolerance induction.
- To understand the underlying immunological mechanisms of the combined therapy.
Main Methods:
- A DA to LEW rat kidney transplantation model was used.
- Rats received FTY720 and/or anti-CD4 mAb RIB5/2.
- Monitoring included serum creatinine, blood lymphocyte counts, and graft analysis via immunohistology, ELISPOT, and RT-PCR.
Main Results:
- Short-term RIB5/2 alone induced long-term graft survival, but FTY720 did not.
- The combination of FTY720 + RIB5/2 abrogated tolerance induction, leading to graft failure and recipient death.
- Combination therapy resulted in enhanced intragraft T-cell infiltration and activation, with reduced protective gene expression.
Conclusions:
- FTY720, while preventing naive T-cell infiltration, may impede the development of regulatory T cells essential for tolerance.
- The combination of FTY720 and anti-CD4 mAb RIB5/2 is detrimental to tolerance induction in this model.
- Therapeutic timing of FTY720 is critical; delayed administration did not interfere with established tolerance.