THE ROLE OF MONOCYTES AND MACROPHAGES IN DELAYED XENOGRAFT REJECTION

Despite the development of successful strategies for averting hyperacu te rejection (HAR) in both small and large animal xenograft models, a delayed xenograft rejection (DXR) ultimately occurs. This process is c haracterized by endothelial cell activation and graft infiltration wit h activated monocytes and natural killer (NK) cells. We evaluated the role of monocytes and macrophages in a guinea pig-to-rat model of DXR. Our results suggest that specific interactions between these cells an d the xenograft occur that result in their activation, since adoptive transfer of xenoactivated splenocytes significantly accelerated both D XR and allograft rejection, while adoptive transfer of alloactivated s plenocytes did not. Furthermore, while normal splenocytes caused antib ody-dependent cell-mediated cytotoxicity (ADCC) of xenogeneic endothel ial cells, xenoactivated splenocytes caused significantly greater endo thelial cytotoxicity by antibody-independent mechanisms. Both normal a nd xenoactivated splenocytes were significantly less cytotoxic if adhe rent cells, consisting predominantly of monocytes and macrophages, wer e first removed. In vivo recipient macrophage depletion, using liposom e-encapsulated dichloromethylene diphosphonate, did not influence DXR and this may indicate that nonphagocytic circulating monocytes may be more important in DXR. However, adoptive transfer of splenocytes from a macrophage depleted, xenoactivated donor did not accelerate xenograf t rejection, while splenocytes from a nondepleted xenoactivated donor did, thereby supporting the importance of monocytes and macrophages in this phase of xenograft rejection.