Platelet-Activating Factor and Hyperacute Rejection

Abstract

The pathogenesis of hyperacute transplantation reactions includes the activation of a cascade of nonspecific inflammatory reactions that precipitates the destruction of the target organ. Platelet-activating factor (PAF) represents an important component of these inflammatory cascades, and we have examined the influence of a specific PAF receptor antagonist (SRI 63-441) on the inhibition of hyperacute rejection in two experimental models, the rejection of rat cardiac allografts by presensitized recipients and guinea pig-to-rat and mouse-to-rat cardiac xenografts. Our results demonstrate that inhibition of PAF function by SRI 63-441 has a variable effect on the survival of cardiac allografts in presensitized rat recipients. In the ACI to sensitized BN cardiac allograft model, the use of SRI 63-441 alone, or in combination with CsA, FK506, or prostaglandin E2 (PGE2), does not prolong graft survival. As we have previously reported, SRI 63-441 does act as a single agent to prolong the survival of ACI to sensitized LEW grafts, and this survival effect is synergistic when combined with CsA. Here we extend these results to demonstrate that this survival is also extended when FK506 is used in the ACI-to-LEW model. Concordant mouse-to-rat cardiac xenografts are also relatively resistant to prolongation of graft survival following treatment with SRI 63-441 alone or in combination with CsA or FK506. Discordant xenografts appear to be more susceptible to inhibition of the rejection reaction with SRI 63-441. When either donor or recipient animals were treated with SRI 63-441 alone, or in combination with CsA or FK506, there was significant prolongation of guinea pig-to-rat cardiac xenograft survival. These results are consistent with our earlier description of the effectiveness of SRI 63-441 in preventing the rejection of cat-to-rabbit kidney xenografts. We believe that these results demonstrate that the use of the SRI 63-441 to specifically interfere with the function of PAF has the effect of prolonging graft survival in those systems in which performed antibody and/or complement activation are important components of the hyperacute reaction. This synthetic drug is representative of a family of compounds whose structure can be modified to balance their therapeutic and toxicity activities, and may prove to be important components of a polytherapeutic approach to the control of graft rejection in sensitized patients or following discordant xenografting.

Effect of a platelet-activating factor (PAF) receptor antagonist on hyperacute xenograft rejection; evaluation in a pig kidney–human blood xenoperfusion model

“…Although in this last work glomerular filtration rate was not measured, the reduction of thromboxane A 2 was associated with a haemodynamic and pathologic benefit. Also, other authors [ 15–18] found that PAF receptor antagonists were able to abolish the full histologic picture of HXR. However, whether these pharmacological agents interfere with the action of complement is controversial [ 22].…”

“…It has been clearly demonstrated that PAF contributes to the pathogenesis of hyperacute allograft rejection in presensitized hosts [ 14]. On the other hand, single administration of PAF receptor antagonists has shown a protective effect in xenograft concordant and discordant models [ 15–19]. However, in some instances PAF antagonists have not provided histologic benefit to HXR [ 20], or they needed to be combined with other agents to prolong xenograft survival [ 21].…”

Factors in Xenograft Rejection

“…In addition, vascular damage, activation of platelets and coagulation with thrombosis within the xenograft vasculature could be exacerbated by the associated loss of vascular ATPDase/CD39, a putative thromboregulatory factor. 69,70 Inhibition of platelet aggregation by treatment of xenograft recipients with antagonists to the platelet fibrinogen receptor, GPIIbIIIa, 80,127 by the use of P-selectin or PAF antagonists, 84,128,129 or by administration of a soluble ATPDase 130 has been generally shown to prolong graft survival in several discordant xenotransplantation models.…”