Modulation of in vivo alloreactivity by inhibition of inducible nitric oxide synthase.

Abstract

Summs~The role of nitric oxide in the immune response to allogeneic tissue was explored in an in vivo cardiac transplant model in the rat. Nitric oxide production during organ rejection was demonstrated by elevations in systemic serum nitrite/nitrate levels and by electron paramagnetic resonance spectroscopy. Messenger RNA for the inducible nitric oxide synthase enzyme was detected in the rejecting aUografted heart, but not in the nonrejecting isografted heart. The enzyme was demonstrated to be biologically active by the in vitro conversion of t-arginine to t-dtrulline and was immunohistochemically localized to the infiltrating inflammatory cells. Treatment with aminoguanidine, a preferential inhibitor of the inducible nitric oxide synthase isoform, prevented the increased nitric oxide production in the transplanted organ and significantly attenuated the pathogenesis of acute rejection. Aminoguanidine treatment prolonged graft survival, improved graft contractile function, and significantly reduced the histologic grade of rejection. These results suggest an important role for nitric oxide in mediating the immune response to allogeneic tissue. Inhibition of inducible nitric oxide synthase may provide a novel therapeutic modality in the management of acute transplant rejection and of other immune-mediated processes. cute rejection is mediated by humoral and cellular immune mechanisms, and is characterized by an intense inflammatory cell infiltrate and progressive destruction of the grafted organ. Despite many recent advances in the understanding of the immune system, the regulatory and effector mechanisms underlying the rejection process remain incompletely understood. Recent reports have demonstrated production of the free radical nitric oxide (NO) 1 during organ transplant rejection (1, 2). NO is synthesized from the amino acid t-arginine by a family of enzymes, the nitric oxide syn-

Upregulation of COX-2 During Cardiac Allograft Rejection

“…43 The cytokine and endotoxin upregulation of COX-2 and iNOS in various cells and tissues is suppressed by dexamethazone and by other immunosuppressive drugs such as cyclosporin A and FK506. 4,10,22,25,44 As mentioned previously, endothelial cell expression of COX-2 may be vasculoprotective by augmenting PGI 2 synthesis. 8 The finding of increased myocardial fibrosis in COX-2 knockout mice suggests that endocardial endothelial cell COX-2 may also be protective by augmenting PGI 2 production.…”

Colchicine-derived compound CT20126 promotes skin allograft survival by regulating the balance of Th1 and Th2 cytokine production

“…Acute allograft rejection represents a typical Th1 response characterized by a predominant production of pro-inflammatory cytokines, IL-2, TNF-, and IFN-, with a low production of Th2 cytokines, IL-4, IL-10, and TGF- (Wu et al, 1992;Strom et al, 1996). Previous studies have also shown that production of NO represents one of the mechanisms participating in graft rejection (Worrall et al, 1995). Kinetics of allograft rejection and the fate of skin allografts correlated with the level of NO or its metabolites produced in the graft (Krulova et al, 2002) and the inhibition of NO production resulted in prolonged allograft survival (Worrall et al, 1995).…”

“…Previous studies have also shown that production of NO represents one of the mechanisms participating in graft rejection (Worrall et al, 1995). Kinetics of allograft rejection and the fate of skin allografts correlated with the level of NO or its metabolites produced in the graft (Krulova et al, 2002) and the inhibition of NO production resulted in prolonged allograft survival (Worrall et al, 1995). Our results showed that CT20126 significantly suppressed the production of NO, TNF-, IL-1 , and IL-2 and failed to effectively inhibit IL-4 and IL-10 in the sponge matrix allograft model (Figure 3).…”

“…The level of NO produced after transplantation correlates with the kinetics of rejection reaction and with the fate of the graft using an experimental mouse model (Krulova et al, 2002). The suppression of NO production from infiltrating macrophages by the specific inhibitor of iNOS resulted in a significant prolongation of survival of skin and heart allografts (Worrall et al, 1995;Krulova et al, 2002).…”

Cell-Based Therapies in the Prevention of Solid Organ Transplant Rejection

“…Also in a rat renal transplant model, liposomal clodronate administration 1 d posttransplantation, which depletes the majority of MΦ, reduces allograft damage (Jose et al, 2003), although liposomal clodronate also depletes other subsets of monocytes and DC thus complicating interpretation of the data. The production of iNOS in particular seems important for allograft rejection, as its neutralization prolongs cardiac allograft survival in mice (Roza et al, 2000;Worrall et al, 1995).…”