There exists convincing evidence that vascularized homografts of solid tissues are destroyed by an immune reaction of the delayed hypersensitive type, and that the lymphocyte plays some crucial role in the genesis of such reactions (1--4). Infiltration by mononuclear inflammatory cells (lymphocytes and histiocytes) is a fundamental characteristic of primary homografts undergoing rejection (5-8), but the question remains as to the precise role which these mononuclear cells play in the destruction of the tissue they have infiltrated. Are they the agents which perpetrate the destruction or are they secondary invaders which have congregated in tissue already injured by some other agency?Recently a number of elegant experiments have shown that specifically sensitized lymphocytes cluster upon and destroy their intended target cells in vitro (9-11), so it does seem that lymphocytes are capable of killing antigenic cells with which they are in contact.The experiments described here and in a preliminary report (12) show that lymphoid cells possess a similar destructive capacity in vivo. The evidence consists of the demonstration that local inoculation of lymphoid cells from inbred parental strain donors is followed by the infiltration and destruction of renal parenchyma in F1 hybrid rats. It will be shown that this reaction develops when the immunogenetic conditions for unidirectional graft vs. host reactions (GVHR) have been met (13), so that humoral antibody and lymphoid cells of host origin cannot play a primary, immunologically specific role in the reaction. Additional experiments which confirm the nature of the observed reaction and which demonstrate the role of lymphocytes of donor origin in it are presented.
A local invasive-destructive reaction typical of that seen in allograft rejection occurs when Lewis rat spleen cells are inoculated under the capsule of Lewis kidney freshly grafted into F(1) hybrid hosts. Thus the donor lymphoid cells can be immunogenically stimulated by circulating host leukocytes and the interaction of these two cell populations results in nonspecific damage to kidney parenchyma. The results indicate that passenger leukocytes in organ allografts may be important immunogenic agents.
Leukemic cells from the blood and marrow of 25 cases of newly diagnosed acute leukemia were presented as target cells to alloreactive effector cells from unrelated normal donors in cell-mediated cytotoxicity assays. In three cases the leukemic targets were poorly killed relative to nonleukemic, HLA-identical target cells. The poor killing of the leukemic cells from one of these cases was shown by competitive inhibition to be due to deficient expression of normal class-I HLA antigens rather than resistance to lysis. Furthermore, the leukemic cells from these three patients were also deficient in binding monoclonal antibodies to nonpolymorphic determinants of class-I HLA and B2 microglobulin. Two additional cases were identified as having a less extensive deficit of HLA, and may be representative of a group with relatively subtle changes in these cell surface antigens. The possible significance of reduced expression of HLA in leukemic progression and in susceptibility to graft-vs-leukemia reactions after bone marrow transplantation is discussed.
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