IMMUNE MECHANISMS IN ORGAN ALLOGRAFT REJECTION

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Abstract
The cellular requirements for rejection of heart grafts bearing isolated major histocompatibility complex (MHC) subregion RT1A-encoded class I disparities was assessed by adoptive transfer. Sublethally irradiated (780 rads) (PVG .times. WF) F1 recipients of irradiated PVG-RT1r1 heart grafts were selectively reconstituted with spleen cells from syngeneic donors previously sensitized with two sequential PVG-RT1r1 skin grafts. PVG-RT1r1 heart grafts were rejected acutely in recipients reconstitued with 10 .times. 106 unfractionated immune spleen cells (7-9 days, n = 6) or inocula (5 .times. 106 cells) depleted of SIg+ cells (10-13 days, n = 5), but additional depletion of cytotoxic T cells and their precursors (0X8+) resulted in marked prolongation of graft survival (n = 4, 4 .times. 106 cells, 45-67 days). Reducing the reconstituting inocula from 4 .times. 106 to 2.5 .times. 106 spleen cells (0X8-, SIg-) prolonged graft survival to that observed in unreconstituted recipients (generally > 100 days). Additional studies were performed of define the immunologic basis for prolonged survival of PVG-RT1r1 heart grafts in homozygous PVG recipients. Although lymphoid cells of naive PVG failed to proliferate (stimulation index [SI] 1.01, P = NS) on coculture with irradiated PVG-RT1r1, bulk cultures yielding but weak and variable CTL generation, lymphoid cells from specifically sensitized PVG proliferated (SI 4.25, P < 0.001) and generated greater cytotoxic T lymphocyte (CTL) activity (P < .001) under identical conditions, strongly suggesting, therefore, that prolonged heart graft survival in this strain combination is related to low CTL precursor frequency. Further, though PVG-RT1r1 heart grafts were rejected in 10-12 days (n = 3) by (PVG x WF)F11 recipients, (PVG-RT1r1 .times. WF)F2 .fwdarw. (PVG .times. WF)F1 heart grafts (RT1Aa disparity) survived > 100 days dispite an equivalent alloimmune response, and this was shown to correlate with a reduced sensitivity of (PVG-RT1r1 .times. WF)F1 target cells to lysis by CTL. These data, therefore, strongly suggest that the pivotal role of CTL in the rejection of class-I-disparate heart grafts is, in fact, related to their function in direct cell-mediated cytolysis.