Negligible role for NK cells and macrophages in delayed xenograft rejection

Abstract

Hyperacute rejection (HAR) of a discordant xenograft can be avoided by complement manipulation, but delayed xenograft rejection (DXR) still leads to graft loss. It is generally assumed that macrophages and NK cells play key roles in DXR. In the present study the survival times and cellular infiltrate following guinea pig to rat heart transplantation was analyzed in the course of DXR, following aspecific and specific manipulation of macrophages and NK cells. HAR was overcome by a single injection of cobra venom factor 1 day before heart transplantation. To aspecifically reduce the inflammatory response dominating DXR, dexamethasone (DEXA) was given. Treatment with DEXA markedly reduced infiltration by NK cells, macrophages, and granulocytes. It also led to prolonged graft survival times (median survival of 0.4 days, n = 10, P< 0.05). In the second series of experiments the specific roles of NK cells and macrophages in DXR were further assessed. Monoclonal antibody 3.2.3 was used to selectively deplete NK cells. Liposome-encapsulated dichloromethylene biphosphonate was given to achieve macrophage depletion. Neither of these specific treatments, alone or combined, led to prolonged graft survival. Immunohistology revealed that at day 2 after transplantation no NK cells or macrophages were present in grafts from the combined treatment group. Only a mild infiltration of granulocytes was observed. Collectively, these results strongly suggest that NK cells and macrophages are not likely to be pivotal cell types in DXR.

The resistance of delayed xenograft rejection to α(1,3)‐galactosyltransferase gene inactivation and CD4 depletion in a mouse‐to‐rat model

“…This discrepancy, as compared to our model, may relate to the genetic manipulations or to the different animal species used, resulting in limited heterologous complement activation (16). Our data are only partly consistent with the findings of Lin et al (17) and van Overdam et al (18), who demonstrated graft infiltration with macrophages and few or sporadic T cells. However, these studies found, in contrast to our results, infiltration of NK cells during DXR.…”

NK‐cell‐dependent acute xenograft rejection in the mouse heart‐to‐rat model

“…However, when all the other components of the immune response to xenografts are intact, depleting NK cells (or macrophages) has no impact on the kinetics or mode of AHXR. So, for instance, in the guinea‐pig heart to cobra venom factor (CVF)‐treated rat model, isolated depletion of NK cells, macrophages or both, has no effect on the time that rejection occurs, although graft infiltration by these cells is appropriately inhibited [15].…”