Permanent CNI treatment for prevention of renal allograft rejection in sensitized hosts can be replaced by regulatory T cells.
Recent data suggest that donor-specific memory T cells (T(mem)) are an independent risk factor for rejection and poor graft function in patients and a major challenge for immunosuppression minimizing strategies. Many tolerance induction protocols successfully proven in small animal models e.g. costimulatory blockade, T cell depletion failed in patients. Consequently, there is a need for more predictive transplant models to evaluate novel promising strategies, such as adoptive transfer of regulatory T cells (Treg). We established a clinically more relevant, life-supporting rat kidney transplant model using a high responder (DA to LEW) recipients that received donor-specific CD4(+)/ 8(+) GFP(+) T(mem) before transplantation to achieve similar pre-transplant frequencies of donor-specific T(mem) as seen in many patients. T cell depletion alone induced long-term graft survival in naïve recipients but could not prevent acute rejection in T(mem)(+) rats, like in patients. Only if T cell depletion was combined with permanent CNI-treatment, the intragraft inflammation, and acute/chronic allograft rejection could be controlled long-term. Remarkably, combining 10 days CNI treatment and adoptive transfer of Tregs (day 3) but not Treg alone also induced long-term graft survival and an intragraft tolerance profile (e.g. high TOAG-1) in T(mem)(+) rats. Our model allows evaluation of novel therapies under clinically relevant conditions.
Institute of Medical Biochemistry and Molecular Biology, University of Rostock, Germany. anja.siepert@med.uni-rostock.de
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A
Siepert
S
S
Ahrlich
K
K
Vogt
C
C
Appelt
K
K
Stanko
A
A
Kühl
J
J
van den Brandt
H M
HM
Reichardt
H
H
Nizze
M
M
Lehmann
M
M
Tiedge
H-D
HD
Volk
B
B
Sawitzki
P
P
Reinke
D019264:Adoptive Transfer; D000818:Animals; D065095:Calcineurin Inhibitors; D005434:Flow Cytometry; D006084:Graft Rejection; D007156:Immunologic Memory; D007166:Immunosuppressive Agents / Q000494:pharmacology*; D016030:Kidney Transplantation; D008212:Lymphocyte Depletion; D051381:Rats; D011917:Rats, Inbred Lew; D020133:Reverse Transcriptase Polymerase Chain Reaction; D050378:T-Lymphocytes, Regulatory / Q000276:immunology*
D065095:Calcineurin Inhibitors; D007166:Immunosuppressive Agents