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Biomedical subjects

E G Neilson

Publications and source records attributed to E G Neilson.

At least 109 records · Page 6Linked to original sources
PubMed1989

T cell recognition of epithelial self.

The presentation of self-antigens to circulating T cells is a critical, precipitating event in the induction of autoimmune injury in parenchymal organs. Epithelia expressing these self-antigens are thought to release such moieties for reprocessing by traditional antigen-presenting cells within the lymphoid system. We now demonstrate, however, that some epithelium possess novel functional mechanisms for presenting their own antigens to a responsive, syngeneic T cell repertoire. The presentation of these self-antigens occurs in the context of MHC class II molecules and depends on CD4 associative-recognition determinants. Our findings strongly suggest that organ epithelium may directly activate cell-mediated events to produce autoimmunity through self-recognition.

Animals↗
PubMed1988

The selection of effector T cell phenotype by contrasuppression modulates susceptibility to autoimmune injury.

The genetic susceptibility to murine alpha TBM disease is a dominant trait that maps to H-2K. In previous studies we have shown that the critical difference between susceptible (SJL) and nonsusceptible (B10.S(8R] mice is the phenotype of the tubular Ag-specific effector T cells (TDTH). In SJL mice, these TDTH are Lyt-2+, whereas in B10.S(8R) mice the TDTH are L3T4+. These phenotypic differences have an important functional correlate: Lyt-2+ TDTH are nephritogenic, whereas L3T4+ TDTH are typically not nephritogenic. Both mouse strains have the potential to differentiate both L3T4+ and Lyt-2+ TDTH. The preferential selection of a single TDTH phenotype in each is the result of differential T cell regulation. In the present studies, we have examined the contribution of suppressor and contrasuppressor T cells in the regulation of TDTH phenotype selection. Our studies show that in both SJL and B10.(8R) mice, after exposure to Ag, a suppressor T cell subpopulation functions to inhibit the nephritogenic Lyt-2+ TDTH. In SJL, but not B10.S(8R) mice, this suppression is counterbalanced by Lyt-2+, Vicia Villosa lectin-adherent T cells. Such contrasuppressor function is mediated through a T cell-derived soluble protein (TcsF), which is Ag-binding and recognized by alpha I-JS antisera. This functional TcsF activity maps, as does susceptibility to disease, to H-2K. In the presence of genetically compatible TcsF, the TDTH phenotype in nonsusceptible mice switches to that of susceptible mice. These Lyt-2+ TDTH from nonsusceptible mice are fully capable of inducing tubulointerstitial nephritis following adoptive transfer. Our studies describe a new role for Tcs cells and augment our understanding of their etiopathogenetic role in autoimmunity.

Animals↗
PubMed1988

Clonotypic heterogeneity in experimental interstitial nephritis. Restricted specificity of the anti-tubular basement membrane B cell repertoire is associated with a disease-modifying crossreactive idiotype.

Experimental anti-tubular basement membrane (anti-TBM) disease is an autoimmune interstitial nephritis elicited in susceptible rodents after immunization with renal tubular antigen. The nephritogenic antigen in the immunizing preparation is 3M-1, a 48,000 Mr noncollagenous glycoprotein. The hallmarks of the renal lesion are the presence of anti-TBM antibodies (anti-TBM-Ab) and a dense mononuclear cell infiltrate. The anti-TBM B cell repertoire in this disease was analyzed using a library of 22 anti-TBM mAbs generated in a prototypically susceptible Brown Norway rat. These anti-TBM mAbs were all demonstrated to be 3M-1 specific and their characterization formed the basis for the following observations: (a) The size of the anti-TBM B cell population is estimated at 58 distinct clones; (b) by competitive inhibition criteria, all anti-TBM mAbs recognize the same (or spatially close) epitope(s) on 3M-1. This focused recognition was maintained in spite of considerable variability in affinity. Epitopic dominance could also be demonstrated in human polyclonal anti-TBM antisera from a patient with anti-TBM disease; and (c) a crossreactive idiotype was documented, and antisera directed toward this set of variable region determinants was shown to be effective as a prophylactic regimen to abrogate disease, and as a therapeutic modality to arrest the progression of disease; (d) analysis of VH gene families suggested biased usage of Q52- and 7183-like families, although at least three gene families are used in the anti-TBM-Ab response. Thus, the anti-TBM B cell compartment in BN rats is moderately large, but is primarily focused to a single epitope on the nephritogenic antigen and is associated with a disease-modifying crossreactive idiotype.

Animals↗
PubMed1988

Murine interstitial nephritis. VIII. Characterization of Igh-V restriction determinants in the development of anti-idiotypic immunity using blocking antibodies.

We have prepared antisera specific for Igh-V-linked determinants (alpha Igh-V) in order to study Igh-V restriction during the development of protective, T cell-mediated anti-idiotypic immunity in autoimmune interstitial nephritis. Suppressor T cells in this network use an antigen-binding (RE-Id+) factor (TsF1) secreted by first-order suppressor cells (Ts-1) to induce an anti-idiotypic (RE-alpha Id+) soluble factor (TsF1) released by effector-phase, Ts-2 suppressor cells. Each of these soluble suppressor factors requires homology in the Igh-V region to complete its regulatory functions. Our alpha Igh-V antisera, adsorbed against network idiotypes, can interfere with the Igh-V restriction used in the induction of Ts-2 suppression by TsF1. The antisera bind both TsF1 and TsF2 in an allele-specific manner and are cytotoxic to induced Ts-2 cells, but not their precursors. These Igh-V determinants appear to behave like activation molecules. They lie outside of the ligand-binding site, do not map with the serologic binding of idiotype, and thus act as distinct associative-recognition elements in the maturation of anti-idiotypic immunity.

Animals↗
PubMed1988

Effects of cyclosporin A on the development of immune-mediated interstitial nephritis.

We examined the effect of daily cyclosporin A administration on the development and extent of tubulointerstitial nephritis produced in rats immunized with tubular basement membranes in adjuvant. Six mg/kg/day of cyclosporin A, given from the time of immunization, completely blocked the development of interstitial lesions and renal insufficiency. The administration of cyclosporin A after the development of interstitial nephritis also arrested the progression of the histological lesions. Both T cell-mediated and humoral immunity were markedly reduced by the administration of cyclosporin A, as evidenced by the near absence of delayed-type hypersensitivity responses and by the reduced production of anti-tubular basement membrane antibodies. Cell admixture experiments indicated that impairment of the delayed-type hypersensitivity response to tubular antigen was probably not the result of active suppression, and suggested that the protective effect of cyclosporin A might be secondary to its direct inhibitory action on the activation of nephritogenic T and B cells. Finally, the treatment of control rats with cyclosporin A, in the doses used, did not produce any detectable kidney damage nor did it impair renal function. We conclude that cyclosporin A can be an effective prophylactic and therapeutic agent in autoimmune interstitial nephritis in rats.

Animals↗
PubMed1988

Characterization of a renal tubular epithelial cell line which secretes the autologous target antigen of autoimmune experimental interstitial nephritis.

Proximal tubular epithelial cells from mice which develop autoimmune interstitial nephritis were found to express the nephritogenic target antigen, 3M-1. Anti-3M-1 mAbs (alpha 3M-1-Ab) were used to positively select for 3M-1-secreting tubular epithelium and, after stabilization in culture, this new cell line (MCT) was examined for the production of several moieties important to either immune interactions or to the development of extracellular matrix. Alkaline phosphatase-staining MCT cells also express epithelial growth factor receptors with a Kd of 0.87 nM and an epithelial growth factor receptor constant (Ro) of 2.1 X 10(4) receptors/cell. MCT culture supernatants contain greater amounts of laminin, and types IV and V procollagens compared to types I and III procollagens, and growing MCT cells on type I collagen matrix causes them to preferentially secrete even more type IV and V procollagen. The 30,000-Mr 3M-1 antigen could be immunoprecipitated from biosynthetically labeled MCT cell supernatants with alpha 3M-1-Ab. An identical-sized moiety was isolated by immunoaffinity chromatography from collagenase-solubilized mouse kidney tubular basement membranes. The 3M-1 antigen can be found on the MCT cell surface by radioimmunoassay, or deposited in a linear array in the extracellular matrix surrounding the MCT cells in culture by immunofluorescence. Mature messenger RNA species for both class I and class II major histocompatibility complex (MHC) molecules were detected by Northern hybridization, and their corresponding cell surface gene products were detected by cytofluorography of MCT cells stained with haplotype-specific antibodies. Both the cell surface 3M-1 and the small amounts of detected class II MHC molecules appear to be biologically functional, as MCT cells can support the proliferation of 3M-1-specific, class II MHC-restricted helper T cells in culture. These findings suggest that MCT cells provide all the necessary biological parameters for interfacing both as the target of a nephritogenic immune response, and as a potential source for new extracellular matrix which develops as a fibrogenic response to interstitial nephritis.

Animals↗
PubMed1988

Elution of kidney-bound antibody by pH-shift does not discriminate between antibodies differing in functional affinity for their ligand.

Antibodies eluted from kidneys by traditional methods of pH shift have been used as reagents in a wide variety of experimental analyses without knowledge of whether their ligand affinity influenced their removal from parenchymal tissue. In the current study we employed two monoclonal antibodies, differing only in their functional affinity (high; K = 2.1 x 10(8)/M and low; K = 6.2 x 10(6)/M) to a common ligand found on the renal basement membrane, to evaluate whether a standard elution technique might selectively facilitate the removal of one antibody over the other. Our findings indicate, however, that the routine methods of elution by pH shift remove both antibodies equally well (41-48%), and without loss of paratypic function. These results provide new evidence that elution by pH shift can produce eluate antibodies which are not biased by preferred affinities.

Animals↗
PubMed1987

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

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.

Animals↗
PubMed1987

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

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.

Animals↗
PubMed1987

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

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.

Animals↗
PubMed1987

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

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.

Age Factors↗
PubMed1987

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

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.

Anti-Bacterial Agents↗
PubMed1987

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

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.

Animals↗
PubMed1987

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

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.

Animals↗
PubMed1987

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

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.

Alprostadil↗