Considerable information is available about the antibody mechanisms that initiate experimental and human renal injury. Despite this knowledge and the use of aggressive therapeutic maneuvers to modulate nephritogenic antibody responses, renal damage often progresses relentlessly to renal failure, necessitating costly and only partially satisfactory measures such as dialysis. Studies herein will examine the humoral and cellular processes leading to progression of immunologically-induced tubulointerstitial nephritis in the rat. This model has an apparent antibody-associated first stage, with sequential stages in which lymphocytes predominate and subsequently monocytes/macrophages, with fibrosis, become prominent. Studies are outlined to determine the major immunopathogenesis of these three stages and to understand how one stage influences the sequential evolution of the next. These include quantitative serum transfer experiments and complement depletion (also polymorphonuclear leukocyte depletion, if needed) to evaluate the first stage. A central question is whether the lymphocytes (predominately T helper cells) in the second stage may be sensitized by the initial injury so that the lesion becomes self-perpetuating. To answer this, selective cell proliferation assays in response to both immunizing and autologous tubular antigens will be done. In addition, subrenal capsule transfer using cells extracted from the active lesions (total cells or populations depleted of T cell subsets or B cells) will be used with or without in vitro antigen-specific propagation and the addition of specific antibody or tubular antigens. These studies coupled with modulation (by specific antisera) of the lymphocyte and macrophage stages will provide an overview of the interrelated facets in the evolution of this model of progressive immune renal injury. The production of the lymphocyte factor, interleukin-2, by the infiltrating cells will be studied since, in association with antigen and accessory cells, it could stimulate local propagation of T cells. Macrophage-produced interleukin-1 will be studied at it may relate to the fibrosis of the later stages of the lesion. An understanding of the elements responsible for the sequential evolution of this lesion and the steps necessary for their interruption will provide a basis for understanding progression and its manipulation in human immune renal injury.
