Allo-specific T-cells encoding for viral IL-10 exert strong immunomodulatory effects in vitro but fail to prevent graft rejection.
Recently, we demonstrated the capacity of allo-specific gene-engineered T lymphocytes as transport vehicle for therapeutic transgenes into allografts. In this study, the influence of viral IL-10 as therapeutic transgene was addressed. Lewis rat T-cell lines specific for DA rat alloantigens were engineered to express vIL-10 by using a retroviral gene expression system. Like T regulatory 1 cells, vIL-10 transgenic T lymphocytes express the phenotype CD4(+)25(+) and secrete, in addition to vIL-10, rat IL-10 and IFN-gamma but no IL-4. First, the capacity of vIL-10 transgenic T-cell lines to modulate alloantigen-specific immune responses was evaluated in vitro. In comparison to control MLR with no transgenic cells or equal numbers of control T(EGFP)-lymphocytes, the proliferation as well as production of IFN-gamma by naive responder cells were significantly diminished. Despite this regulatory capacity in vitro, T(vIL-10)-lymphocytes were not able, either alone or in combination with suboptimal doses of Cyclosporine A, to prolong the survival of either DA rat cardiac or renal allografts in Lewis rat recipients. These data demonstrate that intra-graft IL-10 over-expression is not sufficient to prolong allograft survival in a high-responder strain combination and that the regulatory capacity of T cells in vitro does not predict their in vivo efficiency.
Brandt
Christine
C
Institute of Medical Immunology, Charité- University Medicine, Berlin, Germany.
Yang
Jun
J
Schmitt-Knosalla
Isabella
I
Siepert
Anja
A
Hammer
Markus H
MH
Vogt
Katrin
K
Sawitzki
Birgit
B
Lehmann
Manfred
M
Volk
Hans-Dieter
HD
Ritter
Thomas
T
D000818:Animals; D004797:Enzyme-Linked Immunosorbent Assay; D007108:Immune Tolerance / Q000276:immunology; D016753:Interleukin-10 / Q000276:immunology*; D007519:Isoantigens / Q000276:immunology*; D008297:Male; D016377:Organ Transplantation; D051381:Rats; D011917:Rats, Inbred Lew; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013601:T-Lymphocytes / Q000276:immunology*; D014161:Transduction, Genetic
D007519:Isoantigens; D016753:Interleukin-10