ICOS/B7RP-1 MODULATING SUBSTANCES IN A MOUSE MODEL OF KIDNEY TRANSPLANTATION

Abstract

P1135 Aims: T-cells play a crucial role in inflammatory responses in renal allograft rejection. They are activated by binding of the T-cell receptor to alloantigenic peptides within the MHC II molecule of the antigen presenting cell and costimulation through receptors of the CD28 family. The recently discovered ICOS also belongs to the CD28 family. Signaling via the ICOS receptor with its ligand B7RP1 seems to be responsible for the maintenance of the immune response after the early post-transplantation phase. Regulation of apoptosis could be of importance in such circumstances. Here we investigated the effects of ICOS/B7RP-1 modulating substances in a mouse model of kidney transplantation with regard to apoptosis in the grafts and survival. Methods: Kidneys from Balb-c mice were orthotopically transplanted into BL6 mice (n=16/group). Animals were assigned to five experimental groups: ICOS mAb, ICOS Fc, B7RP-1 mAb, B7RP-1 Fc, and control IgG. The substances were administered i.p. on day –1 prior to transplantation and on days 1, 3, and 5 after transplantation (5 mg/kg). We analyzed the number of apoptotic cells, inflammatory infiltrates, apoptosis regulating factors, and cytokines of the Th1 and Th2 type after five days. Furthermore, survival of the animals was evaluated. Results: Animals receiving ICOS mAb and B7RP-1 Fc had a significantly shorter survival as compared to animals with ICOS Fc, B7RP-1 mAb, and control IgG treatment (Fig.1). Interestingly, the number of apoptotic cells was also significantly lower in animals with ICOS mAb and B7RP-1 Fc treatment (p<0.05). This was paralleled by a shift of bcl-2/bax mRNA towards bcl-2 mRNA coding for the apoptosis inhibiting Bcl-2 in such animals. The Th1 cytokine IFN-γ was significantly higher in ICOS mAb treated animals and tended to be increased in the B7RP-1 treated ones as compared to animals of the other groups. Th2 cytokine levels were not significantly different between ICOS mAb and B7RP-1 groups and control IgG group. Conclusions: Interference with ICOS on activated T-cells could protect such cells from undergoing apoptosis and, thus, could contribute to continuous damage of the graft through ongoing inflammatory processes resulting in accelerated graft loss. This effect was present after perioperative treatment with ICOS mAb and B7RP-1 Fc. Whether such effects are the result of inhibiting or stimulating effects on ICOS and whether treatment at other time points would have different effects in this model remains to be established.