Showing papers by "Eric G. Neilson published in 1987"

Contrasuppression in autoimmunity. Abnormal contrasuppression facilitates expression of nephritogenic effector T cells and interstitial nephritis in kdkd mice.

Abstract: We have used the murine model of spontaneous autoimmune interstitial nephritis in kdkd mice to examine the importance of abnormal immunoregulation in the expression of disease. T cells from naive congenic CBA/Ca mice suppress both histologic renal injury in the kdkd strain as well as the DTH reactivity to CBA/Ca renal tubular antigens mediated by lymphocytes from nephritic kdkd mice. These antigen-specific suppressor T cells are Lyt-2+, L3T4+, I-Jk+, genetically dominant and I-Jk restricted. Unfractionated spleen cells from young, prenephritic kdkd mice also demonstrate such suppressor function. Shortly preceding disease onset, however, net suppression is functionally bypassed by emergent contrasuppressor T cells. These regulatory cells are also Lyt-2+ and I-Jk+, and adhere both to the Vicia Villosa lectin and CBA/Ca TBM. By admixing these contrasuppressor cells with spleen cells from non-disease-prone CBA/Ca mice we were able to demonstrate the presence of DTH-reactive and nephritogenic effector cells in the latter population. Such nephritogenic effector cells could also be simply demonstrated after depletion of the suppressor cells with anti-I-Jk mAbs and complement. These findings support a role for contrasuppressor cells in the abrogation of tolerance to parenchymal self-antigens.

Prostaglandin E1 inhibits effector T cell induction and tissue damage in experimental murine interstitial nephritis.

Abstract: Immunosuppressive effects of E-series prostaglandins have been demonstrated in many in vitro assays of immune responsiveness as well as in autoimmune diseases. To explore the mechanisms underlying prostaglandin E1 (PGE1)-associated immunosuppression in autoimmunity, we treated SJL mice immunized to produce immune-mediated interstitial nephritis with PGE1, PGF2 alpha, or vehicle alone. Mice receiving PGE1 treatment do not develop interstitial nephritis, nor do they display delayed-type hypersensitivity (DTH) to the immunizing renal tubular antigen preparation. The observed immunosuppression is critically dependent on PGE1 administration during the period of effector T cell induction. We therefore investigated the effect of PGE1 on the in vitro induction of DTH effector T cells reactive to renal tubular antigens (SRTA). PGE1 inhibits effector T cell induction in a dose-dependent, reversible manner, but has no inhibitory effect on fully differentiated DTH effector cells or SRTA-reactive cell lines. The PGE1 effect is indirect and mediated via nonspecific suppressor lymphokines. This suppression can be overcome by recombinant interleukin 1 (IL-1), which suggests a mechanism related to either diminished IL-1 secretion or target cell sensitivity to IL-1.

Effector T cell differentiation in experimental interstitial nephritis. I. The development and modulation of effector lymphocyte maturation by I-J+ regulatory T cells

Abstract: Because mice susceptible to interstitial nephritis use different effector T cells than nonsusceptible mice, we analyzed the differentiation process of the effector T cell repertoire by using an in vitro culture technique. In the presence of helper T lymphocytes, accessory cells, IL 2, tubular antigen, and precursor effector cells, both Lyt-2+ nephritogenic effector cells and L3T4+ nonnephritogenic effector cells can be initially induced in both susceptible and nonsusceptible strains within 3 days of culture. In nonsusceptible mice, however, the Lyt-2+ nephritogenic cell is inhibited from further development and disappears, whereas in susceptible mice, its presence is preserved with a resulting effect of tissue destruction. This selection of effector T cell preference is regulated by I-J+ T lymphocytes which are co-functionally expressed with effector cell expansion. Unlike precursor effector lymphocytes, however, the maturation of the regulatory process requires a subset of I-J+ accessory cells and structurally intact tubular antigen. Our findings indicate, therefore, that both susceptible and nonsusceptible mice have the potential for the expression of interstitial nephritis, but nonsusceptible mice are formally protected from autoimmunity by the regulation of lymphocyte preference.

The Limulus amebocyte lysate assay. A rapid and sensitive method for diagnosing early gram-negative peritonitis in patients undergoing continuous ambulatory peritoneal dialysis.

Abstract: • The Limulus amebocyte lysate (LAL) assay was used in a blinded, prospective fashion to analyze peritoneal fluids from 35 consecutive patients undergoing continuous ambulatory peritoneal dialysis (CAPD), who presented with clinical peritonitis. The results were correlated with standard microbiologic culture results. The LAL assay was positive in all three patients with gram-negative peritonitis, was appropriately negative in 24 of 28 gram-positive infections (sensitivity, 100%; specificity, 86%) and was positive in two of five cases in which there was no microbiologic growth. One of the two patients in this last group yielded a gram-negative organism two days later. It was then demonstrated that therapeutic concentrations of a variety of antibiotics (cefazolin sodium, gentamicin sulfate, tobramycin sulfate, ticarcillin disodium, penicillin G potassium, vancomycin hydrochloride, metronidazole hydrochloride, piperacillin sodium, and trimethoprim/sulfamethoxazole) did not interfere with the LAL assay. Together, these data indicate that the LAL assay is useful for identifying patients at high risk for gram-negative peritonitis and for excluding from possible aminoglycoside exposure the majority of patients with peritonitis undergoing CAPD, most of whom will have gram-positive infections. Furthermore, lack of antibiotic interference allows the possibility of monitoring treatment efficacy. ( Arch Intern Med 1987;147:337-340)

Murine interstitial nephritis. VII. Suppression of renal injury after treatment with soluble suppressor factor TsF1.

Abstract: We prepared soluble suppressor T cell factor (TsF1) from donor spleens harvested from mice primed with tubular antigen-derivatized lymphocytes to analyze both its functional interactions with a larger suppressor T cell network and its influence on the nephritogenic effector T cell response producing interstitial nephritis to a parenchymal antigen. Our findings indicate that TsF1 is antigen-specific, genetically restricted by I-J in its direct mediation of suppression, and capable of inhibiting the development of interstitial lesions. TsF1 also provides an inducing signal for the activation of effector Ts-2 suppressors following presentation by accessory cells. The induction of a Ts-2 effect, however, requires that the factor-presenting cell and the recipient of such cells share homology at I-J, and that the TsF1, the precursor Ts-2 cells, and the recipient of the Ts-2 effect share the same Igh-V allotype. Finally, the results of this current report clearly demonstrate a possible therapeutic role for soluble suppressor factors in the management of interstitial renal disease.

Murine interstitial nephritis. VI. Characterization of the B cell response in anti-tubular basement membrane disease.

Abstract: In the present study we have examined the murine B cell response in anti-tubular basement membrane (alpha TBM) disease. Whereas only certain strains of mice are susceptible to the development of interstitial lesions after immunization with heterologous renal tubular antigen, all strains make anti-tubular basement membrane antibodies (alpha TBM-Ab), and all express the 3M-1 kidney antigen which is the target of disease. The magnitude of the alpha TBM-Ab response in serum and renal eluates, measured by radioimmunoassay against crude tubular antigen or affinity-purified 3M-1, also mapped independently of susceptibility. The fine specificity of epitope binding was further analyzed using a rat monoclonal alpha 3M-1 antibody to competitively inhibit the binding of renal eluate antibody to 3M-1. Maximum inhibition among nearly all tested strains ranged from 46 to 56% with no discernible difference between susceptible and nonsusceptible mice. Idiotypic representation of renal eluate alpha TBM-Ab was then evaluated by competitive inhibition using a polymorphic anti-idiotypic antisera. All mice examined possessed almost identical competitive inhibition patterns, indicating surprisingly similar idiotypic representation. Thus, in susceptible or nonsusceptible mice, neither the quantitative alpha TBM-Ab response, the epitopic fine specificity of that response, nor the idiotype of eluted alpha TBM-Ab serve as distinguishing markers for susceptibility to interstitial injury. Finally, passive transfer experiments with high-titered (greater than 1:10,000) alpha TBM-Ab from SJL mice were performed to test the hypothesis that alpha TBM-Ab alone may be sufficient for the induction of alpha TBM disease. Whereas this antiserum was capable of causing typical, severe alpha TBM disease in naive susceptible SJL mice, this treatment in allotype-identical, nonsusceptible B10.S(8R) mice was completely without effect. These data demonstrate, in conclusion, that, in the absence of appropriate susceptibility genes, alpha TBM-Ab are incapable of causing alpha TBM disease. The findings support previous observations that the ability of passively transferred alpha TBM-Ab to initiate interstitial injury is dependent on the host also expressing other susceptibility genes which promote the cooperative engagement of the cell-mediated immune response.

Therapeutic immune regulation in experimental interstitial nephritis with suppressor T cells and their soluble factors.

Abstract: The therapeutic application of immune regulation and suppressor T cells to the control and modulation of autoimmune disease is an area of growing experimental interest. Our group has been studying experimental interstitial nephritis, both to better understand the disease process itself and to test immunoregulatory strategies for their inhibitory and protective effects. This report gives a brief overview of this work.

1,25-Dihydroxyvitamin D3 stimulates interleukin-2 production by a T cell lymphoma line (MLA-144) cultured in vitamin D-deficient rat serum

Abstract: A lymphocyte T cell line (MLA-144), which constitutively secretes interleukin-2 (IL-2), was shown to express receptors for 1,25-dihydroxyvitamin D3 (1,25(OH)2D3). The proliferation of an IL-2-dependent cell line (HT-2) in response to supernatants from MLA-144 cells was employed as an index of IL-2 production by MLA-144 cells. IL-2 production was two fold higher from MLA-144 cells cultured in 2% vitamin D-deficient rat serum compared to 10% fetal calf serum (FCS). The addition of 1,25(OH)2D3 at 10(-15) M or 10(-11) M augmented IL-2 production by MLA-144 cells in vitamin D-deficient rat serum, but not in fetal calf serum. At 10(-7) M 1,25(OH)2D3 there was inhibition of IL-2 production by MLA-144 cells in either vitamin D-deficient serum or FCS. There was no effect of 1,25(OH)2D3 added directly to HT-2 cells. Monoclonal antibody to the IL-2 receptor competitively inhibited the proliferation of HT-2 cells in response to MLA-144 supernatants, suggesting that it was IL-2 from the MLA-144 supernatants which influenced HT-2 proliferation. Our findings demonstrate biphasic dose effects of 1,25(OH)2D3 on lymphokine secretion. The use of vitamin D-deficient rat serum allowed us to demonstrate the effects of 1,25(OH)2D3 in the physiologic and subphysiologic range.

PHYSIOLOGY AND CELL BIOLOGY UPDATE Medullary Cystic Disease: An Inherited Form of Autoimmune Interstitial Nephritis?

Abstract: I NHERITED KIDNEY lesions have historically been classified either by their dominant morphology or by a distinctive functional abnormality. This is because little is really known about their origins or pathophysiology. One consequence of a classification based on morphology is the inevitable tendency to regard diseases with common morphologic features as having shared pathogenic mechanisms, though this mayor may not be true. An enduring example of such a classification system is that of renal cystic diseases. Textbooks on the subject have traditionally grouped together inherited and acquired renal diseases having either macroscopic or microscopic cystS.1.2 Confusion regarding the descriptive nomenclature of cystic diseases is well appreciated, although in the last 10 to 15 years the terminology has become much more consistent. 3 The two most common inherited cystic diseases that typically progress to end-stage are adult polycystic kidney disease (APKD), and the medullary cystic disease-familial juvenile nephronophthisis complex (MCD-FJN). Their patterns of inheritance, natural histories, and associated clinical complications have all been well descibed in recent reports. 4,5 The inheritance of APKD seems to map to the short arm of chromosome 16.6 APKD is typically transmitted with autosomal dominant inheritance, whereas MCDFJN usually follows an autosomal recessive pattern. Together, they account for 10% to 12 % of all end-stage kidney diseases. Although meticulous management of hypertension and infections (especially in APKD) and volume depletion (especially in MCD-FJN) may prevent accelerated loss of renal function, there is no specific therapy for either disease.