Xenotransplantation: DELAYED XENOGRAFT REJECTION

If HAR is averted, xenografts are still rejected in days in­stead of minutes or hours by a process referred to as ‘d­elayed xenograft rejection’ (DXR), also termed ‘acute vascular xenograft rejection’. This process is charac­terized pathologically by infiltration of leukocytes (par­ticularly monocytes and natural killer [NK] cells), focal ischemia and diffuse microvascular coagulation. There is increasing evidence that DXR may be caused by the ongoing interaction of XRA with the graft. Develop­ment of DXR coincides with a marked increase in the syn­thesis of XRA after exposure to xenogeneic cells. Furthermore, removal and/or inhibition of XRA from xe­nograft recipients delays or prevents DXR. In con­trast to HAR, the role of the complement system in the pathophysiology of DXR is unclear. DXR typically occurs in xenograft recipients depleted of complement. Yet the pathologic lesions characteristic of DXR appear to re­flect complement-mediated changes in endothelial struc­ture and function. Hancock hypothesized that even the most potent inhibitors of complement, such as cobra venom factor, are incompletely effective. While such treatments may reduce complement to levels that do not result in HAR, there may still be sufficient complement activity in serum to contribute to the development of DXR. Other possible effector mechanisms for DXR in­clude the action of host platelets and leukocytes on the xe- nograft. Platelets activated by exposure to complement fragments express P-selectin, resulting in the release of po­tent chemotactic signals, such as RANTES and MCP-1, that attract leukocytes, particularly monocytes. The presence of both monocytes and NK cells has been docu­mented in organs with DXR. Treatment of xeno- graft recipients with antibodies that inhibit the function of inflammatory cells has been shown to prolong graft sur­vival. Some studies suggest that NK cells act by dis­rupting the integrity of the endothelial monolayer and by activating endothelial cells. Endothelial acti­vation in animal models of DXR has been associated with a shift to a procoagulant state with induction of tissue fac­tor, production of chemokines such as MCP-1, and induc­tion of leukocyte adhesion molecules such as intercellular adhesion molecule 1.

Figure 1) Pathways for stimulation and inhibition of monocyte/macrophage and endothelial cell procoagulant activity. HDL High density lipoprotein; IDL Intermediate density lipoprotein; IL-1 Interleukin 1; LDL Low density lipoprotein; LPS Lipopolysaccharide; Mac-1 Macrophage 1; MHV-3 Murine hepatitis virus strain 3; MPIF Monocyte procoagulant inducing factor; Th1 T helper 1; TF Tissue factor; TNF Tumour necrosis factor

The Multiorgan Transplant Research Unit at the To­ronto Hospital has an interest in the role of immune- mediated thrombosis in the pathogenesis of DXR (Figure 1). Using a rat liver model of xenotransplantation, we have shown that prophylactic infusion of monoclonal antibod­ies to a cellular procoagulant, fgl-2 prothrombinase, a gly- coprotein that cleaves prothrombin to thrombin, prevents thrombosis, platelet adherence and fibrin deposition. Studies are underway to determine whether organs from
animals in which the prothrombinase gene has been dis­rupted undergo DXR when transplanted into recipient animals. Another potential therapeutic strategy is to vacci­nate animals with soluble prothrombinase so that they may produce neutralizing antibodies to this procoagulant be­fore xenotransplantation. The likely role of endothelial ac­tivation in the pathogenesis of DXR suggests additional approaches for modulating endothelial responses, for ex­ample, by regulated targeting of NF-kappa-B-dependent endothelial cell pathways. In addition, targeting of platelet aggregation and recruitment and activation of host monocytes – early events in the development of DXR – are potential therapeutic approaches.
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Category: Main

Tags: Liver disease, Organ donation, Thrombosis, Xenotransplantation, Zoonosis