Analysis of intragraft effector mechanisms associated with human renal allograft rejection: immunohistological studies with monoclonal antibodies.

Immunohistological studies of rejecting human renal allografts show that the onset of graft rejection is accompanied by the influx of small numbers of T-cells and macrophages. Both cell types occur in focal aggregates adjacent to the Class II antigen-rich renal vasculature and glomerular Bowman's capsule. Although most of the T-cells express the OKT8+ phenotype of cytotoxic T-cells, analysis with markers for activation of T-cells suggests that the vast majority of these cells are present as functionally inactive precursor cells. Smaller numbers of OKT4+ helper T-cells, NK cells and occasional B-cells are also present. Within a few days, up to 15% of T-cells express receptors for IL-2 and other activation markers, suggesting that they are now functionally active. OKT8+ T-cells continue to predominate, but at least some OKT4+ T-cells appear active as DTH cells. A large influx of mononuclear cells, particularly macrophages, follows and these cells are found within and adjacent to the large Class I antigen-rich intertubular capillary network. Many of these intragraft macrophage express pro-coagulant function, presumably through lymphokine-induced activation, and are enmeshed in a fibrin network. Irreversible kidney damage may result from the combined onslaught of these cellular and humoral mechanisms, and examination of nephrectomy specimens suggests that this destruction is principally mediated by macrophages and polymorphs. These studies, by showing the presence of multiple functionally active cell types within rejecting grafts, provide evidence for a multiplicity of intragraft effector mechanisms. This evidence indicates that in addition to cytotoxic T-cells, DTH cells, macrophages, NK, K and B cells contribute to the rejection process. Further unravelling of the complex response and, hence, greater insights into the basis for more effective immunosuppression are likely to follow from the immunohistological application of monoclonal antibodies to rejecting grafts. However, comparison with animal models of kidney rejection already suggests that there may be important differences in both the initiation and effector phases of human kidney allograft rejection.