IMMUNE MECHANISMS IN ORGAN ALLOGRAFT REJECTION: VI. DELAYED-TYPE HYPERSENSITIVITY AND LYMPHOTOXIN IN EXPERIMENTAL RENAL ALLOGRAFT REJECTION

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Abstract
The cellular requirements for renal allograft rejection were reassessed in a rat adoptive transfer model. Transplanted kidneys may be rejected in the absence of cytotoxic T cells or specific antibody. Unilaterally nephrectomized, sublethally irradiated (780 rads) LEW [LEWIS] recipients of renal allografts from irradiated WF [Wistar-Furth] donors, were selectively reconstituted with spleen cells from sensitized syngeneic donors and subjected to delayed nephrectomy of the residual native kidney 3 days posttransplantation. In some experiments the reconstituting inocula were depleted of SIg+ cells (anti-Ig column) or additionally depleted of cytotoxic T cells and their precursors reactive with monoclonal OX8 (rosette depletion). Depleting the reconstituting inocula of SIg+ cells as well as cells reactive with monoclonal OX8 failed (n=4) to alter the tempo of rejection, as demonstrated by a mean serum creatinine .+-.SD on day 8 of 5.4 .+-. 3.8 vs. 6.4 .+-. 4.2 in recipients (n=8) reconstituted with unfractionated inocula. There is a link between DTH [delayed-type hypersensitivity] and graft rejection. Rat lymphotoxin (LT), 1 of the potential mediators of DTH-induced tissue injury was characterized and the presence of LT in rejecting rat renal allografts was demonstrated. Rat LT, generated in vitro by stimulating spleen cells from specifically sensitized rats with keyhole limipet hemocyanin (100 .mu.gm/ml), a MW of .apprx. 50,000. In-vitro-generated rat LT was .apprx. heat stable (70.degree. C for 15 min) and soluble in 40% (NH4)2SO4. Rat LT eluted as a single peak on DEAE anion exchange chromatography (0.015 M, NaCl osmotic gradient), supporting the existence of but a single molecular form. LT was isolated from rejecting renal allografts on day 6 after renal transplant but undetected (< unit) in residual native kidneys. Lymphotoxin, 1 of the potential mediators of tissue injury in this model system, is partially characterized and demonstrated to be present in rejecting rat renal allografts.