Abstracts (complete list) - Wissenschaft Online

Anja Siepert, Birgit Sawitzki, H.M. Reichardt, Jochen van den Brandt, Markus Tiedge,
Manfred Lehmann, Hans-Dieter Volk, Petra Reinke
Low dose CNI treatment can control effector function of
depletion resistant
allo-specific memory T cells (financial support by Else-Kröner-
Fresenius-Stiftung P14/06//A01/06)
Donor-specific tolerance to transplanted tissues remains an elusive goal in clinical
transplantation. Lymphocyte depletion is a commonly used approach in clinical renal
transplantation as part of standard induction immunosuppressive therapy but also
tolerance induction protocols. But preliminary studies in humans have shown that
monotherapies with depleting antibodies can result in severe acute rejection episodes. A
high pool of donor reactive memory T-cells in transplant recipients is considered to be
the main reason for these rejection episodes.
Here we developed an experimental transplant model with an increased allo-specific
memory T cell pool and tested their influence on graft survival and responsiveness to
different therapeutic approaches.
For tolerance induction kidney grafted rats (DA to LEW) were treated with combination
of the depleting mAbs Ox8 (anti-rat CD8; 4 x 1 mg/kg b.w.) and Ox38 (anti-rat CD4; 4
x 10 mg/kg b.w.). Allo-specific memory-like T-cells (15 x 106 cells) were transferred 7
days prior to transplantation. To determine the effect of CNI on memory-like T-cells rats
were treated additionally with short time or permanent low dose CyA (3 mg/kg b.w. d 0-
9 or d 0-150). Serum creatinine and survival of allografted rats were used as read-out
parameters. Graft biopsies from days 5 and 150 pTx were evaluated by
immunohistology.
Long-term function of kidney grafts was maintained by perioperative T-cell depletion
using mAbs Ox8 and Ox38 (MST >150 d). Additional application of allo-specific memory
T-cells resulted in acute rejection in 5 out of 6 rats (MST >12,7 ± 11,8). Despite
inducing strong T-lymphopenia, surviving transferred allo-specific memory T cells can
affect the graft. Short time CyA-application led to prolongation of graft survival time
with a declining transplant function, 4 out of 6 rats died (MST >51,3 ± 24,8). In
contrast, permanent CyA therapy induced long-term acceptance of kidney grafts (MST
> 80 d).
Depletion of T-lymphocyte combined with low dose permanent CyA is sufficient to
control effector function of depletion resistant allo-specific memory T cells.