Innate and adaptive immune responses to nonvascular xenografts: Evidence that macrophages are direct effectors of xenograft rejection

Abstract or Summary

Nonvascularized xenograft rejection is T cell mediated, but is dependent on initial macrophage (M) infiltration. We developed an i.p. transplant model to define the roles of M and T cells in xenograft rejection. Nonobese diabetic or BALB/c mice were injected i.p. with xenogeneic, allogeneic, or syngeneic cells, and the responding cells in subsequent lavages were assessed by flow cytometry and adoptive transfer. Neutrophils and monocytes/elicited M were rapidly recruited in response to xenogeneic pig (PK15 or spleen) cells and, to a significantly lesser extent, allogeneic cells. These innate responses preceded T cell infiltration and occurred in their absence in SCID mice. Syngeneic cells induced negligible neutrophil or M responses. Neutrophils and M induced by xenogeneic cells in SCID mice stimulated T cell recruitment after transfer to immunocompetent mice. T cells in turn were required for M activation and xenogeneic cell rejection. Thus, M harvested from immunocompetent but not SCID mice injected with xenogeneic cells expressed activation markers and rejected xenogeneic cells when transferred into SCID mice. These findings demonstrate the interdependent roles of M and T cells in xenograft rejection. The requirement for M reflects their ability to mount a rapid, local innate response that stimulates T cell recruitment and, having received T cell help, to act as direct effectors of rejection.