Murine interstitial nephritis. IV. Long-term cultured L3T4+ T cell lines transfer delayed expression of disease as I-A-restricted inducers of the effector T cell repertoire.

In the present study we observed that long-term cultures of tubular antigen-reactive L3T4+ T cells from immune SJL mice are able to adoptively transfer interstitial nephritis by 12 wk after i.v. injection. Lesions that develop under these conditions generally occur in the absence of anti-tubular basement membrane antibody formation. These cultured T cell lines are I-A restricted, require L3T4-associative interactions, and are tubular antigen specific, but do not share the phenotype, function, or H-2-restriction characteristics of Lyt-2+ nephritogenic effector T lymphocytes. Rather, our L3T4+ T cell lines, and phenotypically similar lymphocytes harvested from renal infiltrates, are inducers of this Lyt-2+ effector T cell repertoire. Such effector T cells, typically found in immune lymph nodes 4 to 7 days after immunization, can be induced in vitro within 5 days and will acutely transfer disease within another 5 days when placed under the kidney capsule. These findings collectively indicate that the time course for optimal effector cell differentiation and potential expression is relatively short. The immunologic inertia we previously observed between immunization or i.v. adoptive transfer and the development of cellular lesions, therefore, seems to reside in other systemic or interactional events beyond the timely formation of effector T cells.

Spontaneous interstitial nephritis in kdkd mice. I. An experimental model of autoimmune renal disease.

Mice of the kdkd strain predictably develop a spontaneous tubulointerstitial nephritis after 8 wk of life. In this report we have examined several aspects of the nephritogenic immune response that seemed potentially relevant to the expression of this progressively destructive renal lesion. Of particular interest is that by direct immunofluorescence we were unable to demonstrate the presence of antibodies to determinants in the tubulointerstitium. Serum and kidney eluates from nephritic mice, furthermore, did not stain any renal structures in normal kidney. We did observe, however, that disease could be transferred through kdkd----CBA/Ca bone marrow chimeras, and prevented, in the reverse direction, by CBA/Ca----kdkd chimeras. The development of the interstitial lesion was markedly inhibited by thymectomy with T cell depletion, but disease could not be adoptively transferred with cells or serum from nephritic mice. The interstitial lesions also did not appear in (kdkd X CBA/Ca)F1 hybrids, and the development of disease in kdkd mice could be inhibited by treatment with adoptively transferred T cells from CBA/Ca mice. With these new findings we now hypothesize that susceptibility to the expression of interstitial nephritis in kdkd mice involves the cellular limb of the immune system, and may be related, in part, to alterations in regulatory T cell function.

Murine interstitial nephritis. II. The adoptive transfer of disease with immune T lymphocytes produces a phenotypically complex interstitial lesion.

The present studies demonstrate that immune Thy-1.2+, Lyt-1.2+ T lymphocytes harvested from SJL mice with anti-tubular basement membrane disease can adoptively transfer interstitial nephritis into naive recipients. The lesions produced after cell transfer do not occur immediately but rather take 4 to 6 wk to fully develop. Interstitial lesions can also be transferred to a lesser degree and over a longer period of time with immune serum containing anti-tubular basement membrane antibodies. The fully formed lesions that developed after the transfer of immune cells or serum were phenotypically characterized by cell-surface antibodies using immunofluorescence. T lymphocytes, natural killer cells, macrophages, and Ig+ cells were all well represented in both lesions. Natural killer cells, however, were slightly more prevalent in the lesions of mice receiving immune serum. These experiments demonstrate a potential role for both immune T lymphocytes and anti-tubular basement membrane antibodies in the development of interstitial nephritis in mice. Unlike guinea pigs and rats, it is only in mice that interstitial lesions can be adoptively transferred with immune T lymphocytes, and as such, this model should prove very useful in the additional dissection of cellular interactions and immunoregulatory events that formulate the final effector mechanisms of disease expression.

Polymorphism of genes involved in anti-tubular basement membrane disease in rats.

Inbred strains of rats differ widely in their susceptibility to interstitial nephritis induced by rabbit renal tubular basement membrane (TBM) preparations. We now report that susceptibility is determined in part by an RT1-linked gene for effector cell responsiveness producing interstitial lesions. Furthermore, we also obtained evidence that the gene determining expression of the target TBM antigen is linked to the gene for albinism on the first linkage group. When non-susceptible rats lacking the TBM antigen but having the gene for cellular responsiveness were mated with non-susceptible rats which had the TBM antigen but lacked the gene for cellular responsiveness, the F1 hybrids were susceptible to the induction of interstitial nephritis. Although strains varied widely in the amount of anti-TBM antibody (alpha TBM-Ab) they produced, this variation does not appear to be controlled by RT1-linked genes, nor does the isotype or amount of antibody appear to be related to the susceptibility to infiltrating cellular lesions.