Self-regulation of autoreactive kidney-infiltrating T cells in MRL-lpr nephritis.

MRL-lpr kidney-infiltrating (KI) T cell clones (CD3+, TCR alpha/beta+, B220+, CD4-, CD8-) are autoreactive, exclusively proliferate to renal tissues, and secrete interferon-gamma (IFN-gamma). We now report that IFN-gamma treatment of tubular epithelial cells (TEC) decreases their ability to induce KI T cell proliferation. The decreased ability of IFN-gamma-treated TEC to induce T cell proliferation is evident by 24 hours and can be restored by re-exposure to TEC not treated with IFN-gamma. IFN-gamma-treated TEC supernatant does not diminish KI T cell proliferation and IFN-gamma-treated TEC fixed with glutaraldehyde remain less capable of inducing KI T cell proliferation. Although we have not identified the TEC surface molecule(s) modified by IFN-gamma, neither class I, class II, ICAM-1 nor IFN-gamma bound to the surface of TEC are responsible. In conclusion, IFN-gamma induces a surface alteration(s) on TEC capable of limiting their ability to induce KI T cell proliferation. The ability of autoreactive KI T cells to release IFN-gamma represents a self-regulatory mechanism for limiting T cell expansion.

Renal tubular epithelial and T cell interactions in autoimmune renal disease.

Interaction between epithelial cells and T cells may initiate autoimmune tissue destruction. Renal tubular epithelial cells may participate in such immune interactions since they: (1) can be induced to express surface molecules which facilitate engagement with T cells; (2) secrete and express membrane bound cytokines; (3) are exposed to peptides from blood and the glomerular filtrate and are capable of processing these potentially immunogenic peptides. We have recently established T cell clones captured from the interstitium of MRL-lpr mice with lupus nephritis. These T cell clones are unique and are regulated by the lpr gene. They express the alpha/beta T cell receptor, and beta cell markers, but do not display CD4 or CD8 on their surface. These T cell clones proliferate to renal tubular cells but not to cells from other tissues and secrete IFN-gamma which induces class II and ICAM-1 on renal tubular epithelial cells. Expression of class II and ICAM-1 induced by IFN-gamma renders these epithelial cells capable of triggering T cell hybridomas to proliferate and secrete IL-2. Therefore, renal tubular epithelial cells are capable of processing and presenting antigen. This review will focus on the dynamic interaction of renal epithelial cells and T cells and discuss its importance in the initiation of autoimmune renal injury.

Detection of intracellular interleukin-10 by flow cytometry.

Detection of cytokines is limited to measurements of the secreted molecule. To circumvent this problem we permeabilized the cell membrane with digitonin and localize cytokine expression using antibodies by flow cytometry. In this report we demonstrate that we can detect specific intracellular interleukin-10 (IL-10) in the HT-2 T cell line only after membrane permeabilization. With this technique intracellular cytokines are readily detectable.

Autoreactive kidney-infiltrating T-cell clones in murine lupus nephritis.

T-cells have been implicated in autoimmune renal injury. To examine the role of T-cells in lupus nephritis we propagated T-cell clones from the cortical interstitium of MRL/lpr mice. All isolated kidney-infiltrating (KI) T-cell clones [6] express surface markers identical to the T-cells regulated by the lpr gene (Thy 1.2+, TCR alpha/beta +, Lyt-2-, L3T4-, B220+). Although KI T-cell clones have the same surface markers as lymph node-infiltrating (LNI) T-cells, they differ functionally. KI T-cells, but not LNI T-cells, are autoreactive and kidney-specific, exclusively proliferating to renal tubular epithelial (TEC) and mesangial cells. In addition, unlike LNI T-cell supernatants (SN), KI T-cell clones SN induce class II and ICAM-1 on cultured TEC. When KI T-cell clones are injected under the renal capsule, class II is increased on TEC. All clones transcribe mRNA for cytokines capable of inducing class II and ICAM-1 (IL-4, TNF-alpha, IFN-gamma). Anti-IFN-gamma mAb prevents the induction of class II and ICAM-1 on cultured TEC. Since class II and ICAM-1 expression on TEC precedes renal injury, the ability to propagate autoreactive, kidney-specific T-cell clones that induce these molecules provides evidence for their role in initiating renal injury in MRL/lpr mice.

An anergic, islet-infiltrating T-cell clone that suppresses murine diabetes secretes a factor that blocks interleukin 2/interleukin 4-dependent proliferation.

The mechanism of peripheral immunological tolerance has not been fully established. While anergic T cells have been noted in tolerant hosts, the mechanism by which they contribute to the induction and maintenance of tolerance has not been defined. As we previously reported, an accelerated form of diabetogenic autoimmunity in nonobese diabetic mice can be blocked by passive transfer of a CD3+, CD8+, beta-chain variable region 11-positive islet-infiltrating T-cell clone (IS-2.15). In this report we examine the properties of this T-cell clone. We have established that this clone is unresponsive to mitogenic concentrations of anti-T-cell receptor or anti-CD3 monoclonal antibodies and is only weakly responsive to syngeneic islet and spleen cells. Moreover, these T cells secrete an inhibitory factor(s) that irreversibly inhibits interleukin (IL) 2/IL-4-driven proliferation of IL-2/IL-4 indicator T-cell lines. This noncytotoxic factor, which possesses an apparent size of 10-30 kDa, does not interfere with low-affinity IL-2 receptor expression. These data indicate that at least some anergic T cells can play an active role in peripheral tolerance by secreting suppressor factor(s) that regulate IL-2/IL-4-dependent proliferation.

[Renal vasculitis without hematuria in senile patients]. / Vasculitis renal no hematúrica en pacientes seniles.

Systemic vasculitis is a disease whose prognosis has improved considerably with steroid and immunosuppressive treatment, which points up the importance of early diagnosis. In elderly, diagnosis is made more difficult because the frequent onset in the form of a febrile syndrome with non-specific disturbances in general condition. In these patients it is not uncommon that a kidney involvement is what leads to diagnosis of the disease. Hematuria is almost a constant in vasculitis nephropathy. In their absence, acute renal failure in elderly is usually attributed to hemodynamic causes and the frequent presence of iatrogenic tubular factors. This is a report on the case of three elderly patients who presented a febrile syndrome with asthenia, anorexia and weight loss. The three cases progressed to acute renal failure with no disorders in urinary sediment. In two cases was a history of administration of gentamycin, indomethacin and iodated contrast. The clinical diagnosis was toxic and ischemic tubulopathy and, when dialysis became necessary, a renal biopsy was done which showed granulomatous vasculitis, intersticial nephritis and in two cases, necrotizing glomerulitis and crescent formation. Treatment with steroids and cyclophosphamide was started which improved general condition and renal function in one case. Early renal biopsy is advisable in senile patients with non specific systemic symptoms and progressive acute renal failure of unclear origin, even when hematuria is lacking. In this setting, the appearance of underdiagnosed renal vasculitis is possible, and consequent immunosuppressive treatment is a factor for consideration.