Biomedical subjects

C J Kelly

Publications and source records attributed to C J Kelly.

At least 73 records · Page 4Linked to original sources

PubMed1996

Cyclosporine A regulates T cell-epithelial cell adhesion by altering LFA-1 and ICAM-1 expression.

In contrast to the well characterized suppressive effect of cyclosporine A (CsA) on IL-2 gene transcription in T cells, other immunosuppressive effects of CsA have received less attention. We have examined the effect of CsA on the expression of the beta 2 integrin, LFA-1, and its counter receptor, ICAM-1, on a renal Ag-specific murine T cell clone and Ag-expressing renal tubular epithelial cells. We have found that CsA has a concentration dependent effect on the expression of both ICAM-1 mRNA and gene product on renal tubular cells. At 0.1 microgram/ml, CsA exhibits a costimulatory effect, with TNF alpha, on ICAM-1 expression. CsA at 1 to 5 micrograms/ml exhibits concentration dependent inhibition of ICAM-1 cell surface expression by the tubular cells. Although CsA does not inhibit ICAM-1 on T cells, it does inhibit surface expression of LFA-1. The concentration dependent effects of CsA on ICAM-1 expression correlate well with ICAM-1 dependent T cell adhesion to TNF alpha stimulated tubular epithelial cells. TGF-beta 1 has similar effects on ICAM-1 and LFA-1 expression as high dose CsA, but the CsA effects are not mediated through induced TGF-beta 1 expression. Our studies support the conclusion that CsA may bidirectionally alter ICAM-1 dependent cellular adhesive interactions. The inhibition of cytokine stimulated ICAM-1 expression at higher CsA concentrations would contribute to the overall immunosuppressive effect of the drug.

Animals↗

PubMed1995

Role of nitric oxide in lung injury associated with experimental acute pancreatitis.

This study evaluated the effect of varying the synthesis of nitric oxide with sodium nitroprusside or N-nitro-L-arginine methyl ester (L-NAME) in a pancreatitis-lung injury model. Rats (n = 45) were randomized to control or caerulein-induced pancreatitis groups, treated with saline, sodium nitroprusside (0.4 micrograms/kg) or L-NAME (10 mg/kg). Myeloperoxidase activity was used as a measure of neutrophil infiltration. Wet to dry (W:D) lung weight and bronchoalveolar lavage (BAL) protein concentrations were used to assess vascular leakage. Pancreatitis was shown to induce pulmonary neutrophil influx: mean(s.e.m.) myeloperoxidase activity 6.79(0.5) units/g in caerulein-treated animals versus 2.08(0.5) units/g in controls (P < 0.001). Animals with pancreatitis showed increased microvascular leakage compared with controls (mean(s.e.m.) W:D lung weight 7.01(0.5) versus 2.85(0.2), P < 0.001; BAL protein concentration 2539(222) versus 347(32) micrograms/ml, P < 0.001). Compared with the saline-treated pancreatitis group, these changes were reduced by sodium nitroprusside (mean(s.e.m.) myeloperoxidase activity to 2.5(0.4) units/g, P < 0.001; W:D lung weight to 3.8(0.37), P < 0.001; BAL protein concentration 1389(182) micrograms/ml, P < 0.05). L-NAME exacerbated the pancreatitis-induced pulmonary oedema (W:D lung weight increased to 11.96(0.6), P < 0.001), protein leakage (BAL protein concentration rose to 3707(309) micrograms/ml, P < 0.05) and neutrophil infiltration (myeloperoxidase activity increased to 9.01(0.3) units/g, P < 0.05). These data suggest that, in vivo, nitric oxide inhibits pancreatitis-induced lung injury, possibly in part by inhibiting pulmonary neutrophil influx.

Acute Disease↗

PubMed1995

Alpha-1-antichymotrypsin is an effective inhibitor of pancreatitis-induced lung injury.

BACKGROUND: Pancreatitis-induced adult respiratory distress syndrome (ARDS) may result from an imbalance between leucocyte proteases, produced by infiltrating neutrophils, and endogenous protease inhibitors. OBJECTIVE: The aim of this study was to evaluate the role of recombinant alpha-1-antichymotrypsin (rACT P3-P3'), an endogenous serine protease inhibitor, in ameliorating lung injury associated with pancreatitis. DESIGN: Sprague-Dawley rats were randomly divided into control (saline infusion) and pancreatitis groups, which were treated immediately with saline or rACT P3-P3' (50 mg/kg body weight). METHODS: Myeloperoxidase (MPO) was employed as a monitor of neutrophil traffic in the lung, and wet-dry lung weights as a measure of pulmonary endothelial permeability. Lungs were also evaluated histologically. RESULTS: Caerulein (5 micrograms/kg body weight/h) induced pancreatitis in all animals, with an increase in serum amylase from 1851 +/- 208 IU (control) to 5198 +/- 924 IU (pancreatitis), P < 0.05. Pancreatitis caused a significant increase in MPO activity (7.8 +/- 1.1 units compared with 2.08 +/- 0.5 units in controls, P < 0.001) and wet-dry lung weight ratios (12.8 +/- 3.3 compared with 3.2 +/- 0.1 in controls, P < 0.001), indicating significant pulmonary neutrophil influx and microvascular leakage, respectively. These increases in MPO activity and wet-dry ratios were decreased in the pancreatitis group treated with rACT P3-P3' (MPO 4.68 +/- 0.7 units, wet-dry ratio 4.2 +/- 0.5, P < 0.05 compared with the untreated pancreatitis group). CONCLUSION: These data support the hypothesis that deficient endogenous protease inhibition may be responsible for the neutrophil-mediated lung injury observed in pancreatitis and suggest that there may be a therapeutic role for recombinant protease inhibitors such as alpha-1 antichymotrypsin.

Amylases↗

PubMed1994

T cells reactive to an inducible heat shock protein induce disease in toxin-induced interstitial nephritis.

T cells reactive against immunodominant regions of inducible heat shock proteins (HSPs) have been identified in the chronic inflammatory lesions of several experimental autoimmune diseases. Since HSPs are known to be induced by a number of renal tubular epithelial cell toxins associated with chronic interstitial nephritis, we investigated the relevance of HSP expression and T cell reactivity to HSP70 in a model of progressive inflammatory interstitial nephritis. Chronic administration of cadmium chloride (CdCl2) to SJL/J mice induces HSP70 expression in renal tubular cells 4-5 wk before the development of interstitial mononuclear cell infiltrates. CdCl2 also induces HSP70 expression in cultured tubular epithelial cells from SJL/J mice. CD4+, TCR-alpha/beta+ T cell lines specific for an immunodominant HSP peptide are cytotoxic to heat stressed or CdCl2-treated renal tubular cells. Such HSP-reactive T cells mediate an inflammatory interstitial nephritis after adoptive transfer to CdCl2-treated mice at a time when immunoreactive HSP70 is detectable in the kidneys, but before the development of interstitial mononuclear cell infiltrates. T cells isolated from the nephritic kidneys of mice treated with CdCl2 for 13 wk are also cytotoxic to heat shocked or cadmium-treated tubular cells. These kidney-derived T cells additionally induced interstitial nephritis after passive transfer, indicating their pathogenic significance. Our studies strongly support a role for HSP-reactive T cells in CdCl2-induced interstitial nephritis and suggest that the induction of HSPs in the kidney by a multitude of "non-immune" events may initiate or facilitate inflammatory damage by HSP-reactive lymphocytes.

Amino Acid Sequence↗

PubMed1994

Nitric oxide (endothelium-derived relaxing factor) attenuates revascularization-induced lung injury.

Aortic occlusion and revascularization (I-R) may lead to lung injury dependent on activated neutrophil adherence. Nitric oxide (NO) inhibits neutrophil adherence to endothelial cells. We studied the effect of increasing or decreasing NO levels with sodium nitroprusside (SNP) or N-nitro-L-arginine methyl ester (L-NAME) in an I-R lung injury model of 30 min ischemia followed by 120 min reperfusion. Sprague-Dawley rats (10/group) were randomized to controls, I-R, I-R treated with L-NAME (10 mg/ml/hr), and I-R treated with SNP (0.2 mg/ml/hr). Myeloperoxidase activity (MPO) was used as a measure of pulmonary neutrophil influx. Pulmonary endothelial permeability was measured by wet:dry weight ratio and bronchoalveolar lavage protein (BAL prot) and neutrophil counts (BAL PMN). Aortic occlusion and revascularization led to significant increases in pulmonary neutrophil influx (6.1 +/- 0.1 MPO u/g vs 3.05 +/- 0.4 MPO u/g in the control group, P < 0.001) and microvascular leakage; BAL prot (347 +/- 32 mg/ml in controls vs 454 +/- 16 mg/ml in the I-R group, P < 0.05); and BAL PMN (0.7 +/- 0.05 in controls vs 1.8 +/- 0.07 PMN/ml in the I-R group, P < 0.001). These changes were exacerbated further by administration of L-NAME (MPO = 8.9 +/- 0.7; BAL prot = 581 +/- 40 mg/ml; BAL PMN = 2.7 +/- 0.16 PMN/ml). Sodium nitroprusside therapy attenuated the I-R-induced lung injury (3.5 +/- 0.4 MPO u/g, P < 0.05 vs I-R; BAL prot = 330 +/- 61 mg/ml; BAL PMN = 0.9 +/- 0.1 PMN/ml).(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗

PubMed1994

Alterations in macrophage signal transduction pathways mediate post-traumatic changes in macrophage function.

After injury, macrophage effector function diminishes while suppressor function increases. Protein kinase C (PKC), which initiates superoxide synthesis and phagocytosis, and phospholipase A2 (PLA2), which initiates eicosanoid metabolism, are key enzymes in cell signal transduction, which may mediate this change in cell function. The aim of this study was to investigate the effect of trauma on macrophage signal transduction. Swiss-Webster (CFW) mice (n = 210) were randomized to control or hindlimb amputation groups. Animals were sacrificed 24 hr after injury. Peritoneal macrophage function was assessed by measurement of superoxide anion (O2-), Fc, mannose-fucose-mediated phagocytosis, and PGE2 release. Membrane and cytosolic PKC activity were measured by radioimmunoassay in unstimulated and phorbol ester-stimulated cells. Membrane fatty acids and PLA2 activity were measured by thin-layer chromatography. Hindlimb amputation resulted in significantly decreased superoxide anion synthesis (0.7 +/- 0.2 nm vs 1.7 +/- 0.3 nmol/l/10(6) cells in controls, P < 0.01) and phagocytosis and a significant increase in prostaglandin E2 synthesis. This was associated with a shift in cell membrane metabolism with increased PLA2 activity, arachidonic acid turnover, and a significant reduction in PKC membrane translocation in response to phorbol ester. Together these data demonstrate an alteration in signal transduction pathways, which may account for the observed change in macrophage function after injury.

Amputation, Surgical↗

PubMed1994

Immunoregulation and TGF-beta 1. Suppression of a nephritogenic murine T cell clone.

Transforming growth factor beta (TGF-beta) has been clearly linked in several model systems to the development of pathologic extracellular matrix deposition in the glomerulus and interstitium. TGF-beta additionally exerts multiple immunomodulatory effects on T and B lymphocytes, including growth inhibition. Such pleiotropic effects make it difficult to predict how TGF-beta might directionally affect the expression of T cell mediated kidney disease. We have examined the effects of TGF-beta 1 on the activity of effector T cells in a model of autoimmune interstitial nephritis. M52.26 is an antigen-specific, nephritogenic, cytotoxic T cell clone. TGF-beta 1 mediates a concentration-dependent inhibition of M52.26-directed cytotoxicity of tubular epithelial cells in culture, and also of M52.26-mediated transfer of interstitial nephritis to syngeneic recipients. The loss of these functional activities is associated with distinct changes in cytokine gene expression in M52.26. These cytokine alterations consist of a loss of IFN-gamma and perforin expression, and an up-regulation of TGF-beta expression, which is likely relevant to the observed effector T cell inactivation.

Animals↗

PubMed1994

T cell function in chronic renal failure and dialysis.

This article briefly summarizes the literature regarding possible defects in cell-mediated immunity in the setting of chronic renal failure. It is difficult to precisely determine the proximate cause or level of such defects from most studies. Confounding variables include reports on mixed patient populations (predialytic chronic renal failure, hemodialysis patients, and peritoneal dialysis patients) and studies before and after the introduction of erythropoietin for end-stage renal disease patients. While it seems clear that lymphopenia, suboptimal responses to mitogens, abnormal cytokine gene expression, and abnormal IL-2R expression are seen in a number of dialysis patients, the role of uremia versus dialysis in producing these abnormalities is unclear. In addition, it is difficult to determine whether T cell abnormalities are primary or secondary to impaired function of other interacting immune cells, such as macrophages. Clinical implications of defects in cell-mediated immunity are additionally discussed.

Gene Rearrangement, T-Lymphocyte↗

PubMed1994

Molecular analysis of the helper T cell response in murine interstitial nephritis. T cells recognizing an immunodominant epitope use multiple T cell receptor V beta genes with similarities across CDR3.

Anti-tubular basement membrane disease (alpha TBM disease) produces T cell-mediated interstitial nephritis in SJL mice after immunization with renal tubular antigen. Initial mononuclear infiltrates appear in vivo after several weeks, with the subsequent progression to renal fibrosis and end stage renal disease over many months. We have analyzed the fine specificity of the autoreactive helper T cell repertoire in alpha TBM disease through the isolation and characterization of a panel of CD4+ Th1 clones harvested after 1-2 wk from animals immunized to produce disease. All clones capable of mediating alpha TBM disease are directed towards a 14-residue immunodominant epitope (STMSAEVPEAASEA) contained within the target antigen, 3M-1. Evaluation of the T cell receptor (TCR) V beta repertoire used by these autoreactive T cells reveals the use of several V beta genes, but with some preference for V beta 14. Sequencing across the putative CDR3 region of the TCR beta chains suggests that common amino acids at the V beta(N)D beta junction and the D beta(N)J beta junction may contribute to the specific ability of these cells to recognize the immunodominant epitope.

Amino Acid Sequence↗

PubMed1994

Inhibition of murine nephritogenic effector T cells by a clone-specific suppressor factor.

We have used a murine model of organ-specific autoimmunity to characterize therapeutic modalities capable of down-regulating the cellular limb of the autoimmune response. Murine interstitial nephritis is an autoimmune disease mediated by tubular antigen-specific CD8+ nephritogenic effector T cells which are delayed-type hypersensitivity (DTH) reactive and cytotoxic to renal epithelial cells. Previous studies have demonstrated that disease can be suppressed with experimentally induced populations of T cells (Ts1 and Ts2 cells) obtained after injection of tubular antigen-coupled splenocytes into syngeneic mice. As the target of Ts2 is the CD8+ effector T cell, we have evaluated its effects on nephritogenic effector T cell clones isolated from diseased animals. Our studies demonstrate that soluble proteins expressed by Ts2 cells (TsF2) specifically abrogate the DTH, cytotoxic, and nephritogenic potential of M52 cells, although T cell receptor and IL-2 receptor expression are unchanged in these unresponsive M52 clones. TsF2-induced inhibition is dependent on new mRNA and protein synthesis. In a cytotoxic clone, M52.26, exposure to TsF2 induces expression of TGF-beta 1 which is, in turn, required for inhibition of cytotoxicity and nephritogenicity. Our studies are consistent with TGF-beta 1 behaving, at least in some T cells, as a nonspecific final effector of clone-specific suppression.

Amino Acid Sequence↗

PubMed1994

Inherited interstitial nephritis in kdkd mice.

kdkd mice, a mutant subline of CBA/Ca mice, develop a progressive, T cell-mediated, autoimmune interstitial nephritis which leads to renal failure and death of all mice at 20-28 weeks of age. This disease is inherited in an autosomal recessive manner, with complete penetrance, and has been linked to grizzled and waltzer on mouse chromosome 10. Immunologic evaluation of this lesion has demonstrated that histologic disease is initiated by a population of CD8+, H-2Kk-restricted T cells, which recognize an antigen in collagenase-solubilized syngeneic renal tubules. These nephritogenic effector cells can also be demonstrated in non-disease prone CBA/Ca mice. Susceptibility to autoimmune nephritis correlates with distinct expression of regulatory, rather than effector, T cells. Interstitial nephritis in kdkd mice can be inhibited by protein-calorie restriction, infusions of CBA/Ca CD8+ T cells, or monoclonal antibodies of ICAM-1. This murine model most closely resembles medullary cystic disease in humans, which has not historically been considered an autoimmune disease. Mapping of the genes for both medullary cystic disease and the defect in kdkd mice should augment our understanding of mechanisms of organ-specific autoimmunity.

Animals↗

PubMed1993

Macrophage-dependent candidacidal mechanisms in the murine system. Comparison of murine Kupffer cell and peritoneal macrophage candidacidal mechanisms.

Candida albicans infection is common in immunocompromised patients. The role of fixed tissue macrophages (M phi), including Kupffer cells (KC) and peritoneal macrophages (PM phi), in host defense against C. albicans is unclear. This study examined murine M phi candidacidal mechanisms and evaluated the in vitro role of the macrophage-activating factor IFN-gamma in augmenting these mechanisms. The effect of in vivo administration of IFN-gamma on survival after lethal C. albicans challenge in the murine system was also assessed. Percent PM phi and KC ingestion of C. albicans were similar. Prior opsonization of Candida increased the percentage of M phi ingestion of this pathogen. PM phi and KC phagocytic function was similar for both nonopsonized and opsonized C. albicans, but KC demonstrated markedly decreased ability to kill this pathogen (O2-, Candida killing). IFN-gamma enhanced KC and PM phi candidacidal activity. PM phi and KC Ag presentation was increased in early Candida infection, but diminished in established infection, when the majority of animals died. C. albicans failed to elicit significant amounts of either IL-1 or TNF compared with LPS stimulation of PM phi and KC in vitro. IFN-gamma treatment in vivo was associated with significantly improved survival (p < 0.01).

Animals↗

PubMed1993

Role of bactericidal permeability-increasing protein in the treatment of gram-negative pneumonia.

BACKGROUND: Gram-negative infections are a major cause of morbidity and death. Bactericidal permeability-increasing protein (BPI) is an endotoxin-neutralizing protein that also exhibits potent bactericidal activity. This study compared the efficacy of a 23 kd recombinant N-terminal fragment of BPI (rBPI23) with that of antiendotoxin antibody E5 in a model of gram-negative sepsis. METHODS: Sixty Swiss-Webster mice (Carworth farm) received an intratracheal inoculation of Escherichia coli (7 x 10(6) colony-forming units) and were randomized to three groups (20 per group). Starting immediately after inoculation, the groups received either rBPI23 (4 mg/kg intravenously every 2 hours for four doses), E5 (11 mg/kg intravenously every 24 hours for two doses), or an isotype control antibody B55 (11 mg/kg intravenously every 24 hours for two doses) and were followed up for survival. In a second survival study, 40 mice received the same intratracheal inoculation of E. coli and were randomized to two groups. Starting 2 hours after inoculation, the groups received either rBPI23 (4 mg/kg intravenously every 2 hours for four doses) or E5 (8 mg/kg intravenously every 12 hours for four doses) and were followed up for survival. In a third study, mice received an intratracheal inoculation of 3 x 10(6) colony-forming units E. coli, a sublethal dose, and were killed to determine pulmonary and blood clearance of bacteria. RESULTS: rBPI23 conferred significantly greater protection from death than either E5 or B55 when started immediately (95% survival vs 20% and 10%, respectively; p < 0.001) or 2 hours after inoculation (65% survival vs 25% for E5; p < 0.05). Both pulmonary and vascular clearance of bacteria was enhanced significantly by treatment with rBPI23. CONCLUSIONS: rBPI23 may be a novel therapeutic agent in the management of gram-negative sepsis.

Animals↗

PubMed1992

Colorectal cancer. Principles of postoperative follow-up.

Monitoring patients after primary large bowel surgery for malignancy is predicated on the concept that early detection of recurrence may provide salvage treatment for cure. Knowledge of the pathologic site and stage provides important information as to the probability of recurrence and the patterns of failure that are likely to occur. Available methods to detect recurrence include clinical, roentgenographic, and serum tests that are done more frequently during the first 2 years after surgery. Monitoring plasma carcinoembryonic antigen levels can lead to identification of asymptomatic recurrences, but there is controversy about the curability of recurrences outside the liver. Newer techniques (such as computed tomographic portography, intraoperative ultrasonography, and radioimmunoguided surgery) provide greater diagnostic accuracy and lead to more appropriate procedures during "second-look" operations. For example, hepatic resection in properly selected patients offers up to a 30% chance of cure and should be pursued aggressively. A search for metachronous cancers by endoscopy also should be done. Knowledge of the potential and patterns of failure can provide a useful guide during the postoperative follow-up care of the patient with large bowel cancer.

Colorectal Neoplasms↗

PubMed1992

Anti-neoplastic effects of interleukin-4.

Interleukin-4 (IL-4) is a cytokine, with potential anti-neoplastic effects. This study examined the effects of IL-4 on host anti-tumor responses in a murine model. C57/B16 mice (n = 40) were randomized to receive Lewis lung carcinoma (10(6) cells: right flank; sc) or saline, and sacrificed 10 days postinoculation for assessment of peritoneal macrophage (PMO) anti-tumor mechanisms [superoxide anion generation (O2-), tumor necrosis factor (TNF), and TNF-independent (P815) cytotoxicity], splenocyte mixed lymphocyte response (MLR) (Balb/c stimulator), and cytotoxic lymphocyte generation (CTL against P815). Cells were cultured +/- IL-4 (100 U/ml). In a second study, 20 mice received Lewis lung implants (sc) and were randomized on Day 21 to receive daily IL-4 (1000 U/mouse; ip) or saline. Tumor volumes and median survival were assessed. Tumor necrosis factor-independent cytotoxicity (O2-, MLR and CTL) was impaired in the tumor-bearing (TB) study group. Interleukin-4 administered to cultured cells from TB mice enhanced O2-, as well as MLR and CTL (P less than 0.01), and decreased TNF release but did not alter PM phi TNF-independent anti-tumor responses (P815). In vivo administration of IL-4 significantly decreased tumor growth (P less than 0.05) after 10 days of treatment and significantly prolonged median host survival (P less than 0.05). These findings indicate the therapeutic potential of IL-4 in the TB host which may function through downregulation of TNF production while potentiating certain T cell-dependent and independent anti-tumor immune mechanisms.

Animals↗

PubMed1992

Tubular antigen-binding proteins repress transcription of type IV collagen in the autoimmune target epithelium of experimental interstitial nephritis.

We have been studying immune interactions with somatic cells using a tubular antigen-binding protein (ThF) secreted by helper T lymphocytes harvested from mice that have an autoimmune form of interstitial nephritis called anti-tubular basement membrane disease. This ThF, although characterized originally because of its ability to induce effector T cells, additionally recognizes the nephritogenic 3M-1 antigen expressed by its target renal tubular epithelium. We believe these proteins, in general, may modulate directly some homeostatic functions in organ-derived cells, and now report that our ThF represses specifically the cellular transcription and secretion of basement membrane type IV collagen in tubular epithelium. These in vitro findings of reduced levels of mRNA encoding type IV collagen correlate well with in situ hybridization studies performed on kidneys expressing early autoimmune lesions, and predict a progressive drop in the expression of type IV collagen in the interstitium. Such a novel and unexpected repression of transcription of type IV collagen might easily impart or facilitate permanent change in the infrastructure of kidney architecture during autoimmune injury and, perhaps, contributes to the process of tubular atrophy attendant to prolonged renal inflammation.

Animals↗

PubMed1992

Effects of laparotomy on systemic macrophage function.

Surgical trauma induces immunosuppression that may adversely influence survival. This study examined the effect of laparotomy on two different macrophage populations, peritoneal macrophages (PM phi) and Kupffer cells. Female, 6- to 8-week old, CFW/C3H-HeN mice (n = 160) were randomly allocated to one of three study groups: control, ether anesthetic only, or ether anesthetic and laparotomy. On postoperative days 1 and 3, PM phis and Kupffer cells were harvested and assayed for superoxide anion production (O2-), percent macrophage phagocytosis of Candida albicans (CAP), percent C. albicans killed by macrophages (CAK), percent major histocompatibility complex (MHC)-class II antigen expression, and antigen presentation. Macrophages isolated on postoperative day 1 were also cocultured with 100 units/10(6) cells/ml interferon-gamma (IFN-gamma). Laparotomy significantly impaired microbicidal activity (O2-, percent CAP, and percent CAK) and antigen presentation on postoperative day 1. On postoperative day 3, O2- and antigen presentation were increased significantly (p less than 0.05) over control values, indicating a rebound phenomenon. Kupffer cell microbicidal function was unchanged on postoperative days 1 and 3. The initial immune impairment (PM phis: O2-, CAP, and CAK) was abrogated by IFN-gamma treatment. In immunosuppressed hosts after injury, administration of macrophage-activating factors such as IFN-gamma could be of therapeutic benefit.

Animals↗

PubMed1991

Molecular characterization of a major nephritogenic domain in the autoantigen of anti-tubular basement membrane disease.

Anti-tubular basement membrane (alpha TBM) disease is a form of primary interstitial nephritis mediated by autoimmune T cells and alpha TBM antibodies. In mice and humans the nephritogenic immune response is directed to a glycoprotein (3M-1) found along the proximal tubule of the kidney. We have isolated cDNAs from an expression library that encodes for the common framework domain of the 3M-1 antigen. This common domain was once related evolutionarily to a family of intermediate filament-associated proteins. Northern hybridization revealed that all isoforms of 3M-1 range between 1700 and 1900 base pairs and in situ hybridization studies indicate that transcripts are found in tubular epithelium. Candidate peptide fragments were deduced and synthesized from the sequence encoding this common framework domain, and one of the peptide residues was able to bind a monoclonal 3M-1-reactive alpha TBM antibody, stimulate the growth of 3M-1-reactive helper T cells, and induce nephritogenic effector T cells capable of producing interstitial nephritis. Our results indicate that a unique, immunodominant region of the 3M-1 antigen is an informative participant in the emergence of autoimmune injury to certain basement membranes.

Amino Acid Sequence↗