FTY720 prevents anti-CD4 mAb-induced tolerance but cannot reverse established tolerance in a rat kidney transplantation model.
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.
Schroeder
Grit
G
Institute of Medical Biochemistry and Molecular Biology, University of Rostock, Germany. grit.schroeder@med.uni-rostock.de
Risch
Kirsten
K
Kotsch
Katja
K
Siepert
Anja
A
Brock
Josef
J
Nickel
Peter
P
Reinke
Petra
P
Ritter
Thomas
T
Volk
Hans-Dieter
HD
Lehmann
Manfred
M
D000818:Animals; D000911:Antibodies, Monoclonal / Q000627:therapeutic use*; D001706:Biopsy; D015704:CD4 Antigens / Q000276:immunology*; D003404:Creatinine / Q000378:metabolism; D004359:Drug Therapy, Combination; D000068876:Fingolimod Hydrochloride; D006085:Graft Survival; D007166:Immunosuppressive Agents / Q000627:therapeutic use*; D016030:Kidney Transplantation / Q000276:immunology*; D018655:Lymphocyte Count; D008297:Male; D023421:Models, Animal; D016133:Polymerase Chain Reaction; D011409:Propylene Glycols / Q000627:therapeutic use*; D051381:Rats; D011917:Rats, Inbred Lew; D013110:Sphingosine / Q000031:analogs & derivatives; D013601:T-Lymphocytes / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D023001:Transplantation Tolerance / Q000187:drug effects; D014511:Uremia / Q000209:etiology
D000911:Antibodies, Monoclonal; D015704:CD4 Antigens; D007166:Immunosuppressive Agents; D011409:Propylene Glycols; D003404:Creatinine; D000068876:Fingolimod Hydrochloride; D013110:Sphingosine