Biomedical subjects
Publications and source records attributed to R M Lewis.
The immunopathogenic mechanisms responsible for myasthenia gravis, polymyositis, masticatory myopathy, and dermatomyositis are discussed in light of their relevance to the clinical disease. Current thinking concerning these disorders is presented as a prelude to further research and greater understanding.
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The site at which the vasomotor effects of cyclosporine are associated with acute nephrotoxicity appears to be the afferent arteriole. Proposed mechanisms mediating these effects include sympathetic nerve stimulation, disruption of the balance between vasodilating and vasoconstricting prostaglandins, hypersensitivity to vasoactive peptides, and endothelin release. These mechanisms mediate cyclosporine-associated intrarenal vasoconstriction, yet the causal relationship between these changes and the obliterative vasculopathy seen in association with chronic progressive renal allograft dysfunction is uncertain. Histologic findings seen in chronic progressive renal dysfunction are nonspecific and cannot be correlated solely with cyclosporine use. Retrospective studies analyzing both aggregate serial serum creatinine and reciprocal creatinine determinations did not report a pattern of progressive attrition consequent to toxic nephropathy. Prospective studies with serial GFR determinations with various reference substances found no progressive deterioration in allograft function. Both the retrospective and prospective studies indicate that the attrition of renal allograft function associated with cyclosporine use reflect the chronic effects of immunologic injury. Renal function in extrarenal transplant recipients immunosuppressed with cyclosporine can be characterized by an initial decline in native renal function followed by subsequent stabilization beyond the first 6 months. There does not appear to be an inordinate rate of progression to ESRD.
PURPOSE: This study was done to quantitate the biologic effects of different wavelengths of radiation in the UVA- and UVB-wavelength region on cultured rabbit lens epithelial cells. METHODS: An action spectrum for UV-induced cytotoxicity as measured by colony-forming ability was determined using six different monochromatic wavelengths from 297 to 405 nm in rabbit lens epithelial cell line N/N1003A. Cell survival was determined by clonogenic assay. Fluence rates were monitored with a calibrated radiometer. RESULTS: Survival curves show that cell killing was most efficient at 297 nm. After quantum correction, the efficiency of 297-nm radiation in cell killing was 7 times greater than was 302-nm radiation. Radiation at 297 nm was more than 170, 340, 560, and 2000 times as effective in cell killing as 313-, 325-, 334-, and 365-nm radiation, respectively. The action spectrum had a shape similar to the DNA absorption spectrum in the UVB region, suggesting that DNA may be one of the critical targets for damage to the cells. At wavelengths longer than 313 nm, the shape of the action spectrum deviated from the DNA absorption spectrum. CONCLUSIONS: Cytotoxicity of UV radiation in cultured lens epithelial cells varies greatly with wavelength within the UVA and UVB regions. Different mechanisms may predominate in the two wavelength regions. Cultured cells may provide a suitable system for investigating the mechanisms by which UV radiation damages lens epithelial cells and leads to cataract formation.
Immunosuppressive agents may initiate their pharmacologic action by disrupting phosphorylation cascades critical to T lymphocyte intracellular signaling after alloantigen recognition. Activator of DNA Replication (ADR), a transduction signal sensitive to CsA as well as rapamycin (RAPA) immunosuppression, seemed a likely candidate for phosphoregulation. This communication reports the development of a cell-free assay wherein CsA and RAPA inhibit ADR induction by protein kinase C (PKC). ADR and PKC are inactive in the cytosol of resting cells. Endogenous PKC activity in quiescent lymphocytes was triggered with the tumor promoter PMA, leading to the appearance of ADR, an event subsequently quantitated by the ability of ADR to trigger [3H]thymidine triphosphate incorporation into isolated nuclei. After PKC induction, ADR activity is increased (890 +/- 120 vs. 3910 +/- 345 cpm, P < 0.001). In the presence of the PKC inhibitor H7, ADR activity fails to increase (100 +/- 50 vs. 3910 +/- 345 cpm, P < 0.001). The high levels of ADR found in PHA-stimulated cells is marginally affected by in situ PKC induction, although the sustained impact of H7 throughout the cell cycle suggests that ADR is constantly being phosphorylated. Titration of CsA or RAPA into the cell-free system inhibited ADR induction in a dose-dependent fashion. The utility of ADR induction as a marker for immunosuppression was investigated by comparing ADR inducibility in resting cells that had been preloaded with CsA or RAPA with the proliferative index of cells cultivated with CsA or RAPA. ADR induction directly correlated with CsA or RAPA proliferative inhibition. The results suggested that ADR is a constituent of the PKC phosphoregulatory cascade essential for cell cycle progression. The correlation between cell-free ADR inducibility and proliferative inhibition by CsA or RAPA suggest that this procedure may be useful for in vitro prediction of allografted patient immunologic response.
Distribution of cadaveric donor kidneys, based upon the donor-recipient HLA match grade, remains one of the major controversies in transplantation. To determine whether matching results in fewer rejection episodes and better graft survival, we retrospectively studied our single-center patient population of 683 cyclosporine-prednisone-treated primary cadaveric renal allograft recipients. For 237 recipients of well-matched HLA A, B kidneys (< or = 2 HLA A, B mismatches [MM]) the 1-, 3-, 5-, and 7-year graft survivals of 76%, 66%, 62%, and 61%, respectively, were not significantly different from those of 71%, 65%, 63%, and 63%, respectively, for the 446 poorly matched HLA A, B (> 2 HLA A, B MM) recipients. Similarly, the 1-, 3-, 5-, and 7-year graft survivals for the 307 recipients of well-matched HLA-DR kidneys (0 or 1 DR MM) of 74%, 65%, 63%, and 61%, respectively, were not significantly different from those of 72%, 65%, 63%, and 62%, respectively, for the 366 poorly matched (2 DR MM) recipients. Patient survivals were comparable at each time point for well- vs. poorly matched recipients. Similarly, donor-recipient HLA A, B, and DR matching was not beneficial in retransplant recipients who were transplanted following negative NIH and antiglobulin (AHG) crossmatches when testing both historical (high-PRA) and pretransplant sera. Since rejection episodes may be a more sensitive indicator of immune response than graft loss, we also analyzed the relationship between donor-recipient HLA match grade and posttransplant rejections. A total of 60% (n = 413) of recipients experienced no rejections and had 1-, 3-, 5-, and 7-year graft survivals of 82%, 78%, 74%, and 73%, respectively; 32% (n = 215) of patients who experienced 1 rejection had 1-, 3-, 5-, and 7-year graft survivals of 58%, 48%, 44%, and 43%, respectively (P < 0.001 for graft survival of 0 vs. 1 rejection). The remaining 8% (n = 55) of recipients experienced more than 1 (> 1) rejection and had 1-, 3-, 5-, and 7-year graft survivals of 62%, 38%, 36%, and 36%, respectively (P < 0.001 for graft survival of 0 vs. > 1 rejection and P < 0.01 for graft survival of 1 vs. > 1 rejection). The mean numbers of rejections/patient experienced by well-matched vs. poorly matched recipients were comparable and not significantly different.(ABSTRACT TRUNCATED AT 400 WORDS)
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DARPP-32 (dopamine- and adenosine 3',5'-monophosphate-regulated phosphoprotein of Mr = 32,000) mRNA distribution was examined in adult mouse central nervous system by in situ hybridization. In general, DARPP-32 mRNA was found in regions of brain where cells express the dopamine D1 subtype receptor. Cells of the olfactory tubercle, caudate-putamen, and nucleus accumbens had the highest levels of DARPP-32 mRNA, as did choroid plexus and Purkinje cells. Relatively high levels were found in medial habenula and lateral piriform cortex. Moderate levels were seen in cerebral cortex layer VI, medial piriform cortex, lateral entorhinal cortex, tenia tecta, anterior olfactory nucleus, and lateral bed nucleus of the stria terminalis. Low levels were observed in hippocampus, cerebral cortex layers II and III, olfactory bulb, and the nucleus of the lateral olfactory tract. DARPP-32 mRNA levels in the amygdaloid nuclei varied greatly.
A 12-year-old thoroughbred gelding died from diffuse global glomerulonephritis, 3 months after a lower respiratory infection from which Streptococcus zooepidemicus was isolated. Immunopathological studies (immunofluorescence, immunodiffusion, immunoperoxidase testing and immunoblotting) indicated the presence of an immune reactant renal disease associated with IgG antibody and streptococcal antigens.
Data from the Office of the Inspector General and the United Network for Organ Sharing suggested that black end-stage renal disease patients had unequal access to organ transplantation, in that they waited twice as long as white ESRD patients for a renal transplant. We hypothesized that preTx histocompatibility factors were more influential in determining how quickly an ESRD patient was transplanted than had been realized by either the Office of the Inspector General or UNOS. To test this hypothesis we compared the crossmatch reactivity of 378 white and 227 black ESRD patients awaiting a primary renal Tx against 100 consecutive cadaveric donors (80 white, 10 black, and 10 Mexican-American). A positive XM frequency of 16% (179 positive XM/1121 total XM) was observed when white ESRD patients were crossmatched against white donors. A comparable frequency of 21% (39/186) (+) XM was observed when white ESRD patients were crossmatched against black donors. Similarly, black ESRD patients crossmatched against black donors showed a 17% (20/115) (+) XM frequency. In contrast, a significantly higher (+) XM frequency of 43% (283/655) was observed when black ESRD patients were crossmatched against white donors (P less than 0.001). When black ESRD patients with a (+) preTx blood transfusion history were crossmatched against white donors, a 55% (241/438) (+) XM frequency was observed. This (+) XM frequency was 3.2 times greater than when black ESRD patients were matched against black donors (P less than 0.001). However, when untransfused black ESRD patients were matched against white donors only a 19% (42/217) (+) XM frequency was observed. Finally, preoperatively transfused black ESRD patients displayed a higher PRA of 47 +/- 12% vs. 27 +/- 10%, P less than 0.01, and a longer median waiting time to transplant of 329 vs. 181 days, P less than 0.01, than comparable white patients. The data suggest that presentization of blacks, following preTx blood transfusions from nonblack donors, predisposes black ESRD patients to present as immunologically inappropriate recipients for predominantly white donor allografts and results in their spending a longer time on renal transplant waiting lists.
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Retrospective analysis of necropsy findings of 705 woodchucks was performed to determine the prevalence and morphology of immune-mediated glomerulonephritis, its relationship to woodchuck hepatitis virus (WHV) infection, and the presence of major WHV antigens. Twenty-six woodchucks had glomerular lesions. Renal tissue of the 26 animals was evaluated histologically and immunohistochemically for immune-mediated glomerulonephritis. Of these 26 animals, immune-mediated glomerulonephritis was diagnosed in six, all of which were chronic WHV carriers. Membranous glomerulonephritis was identified in three animals, two of which also had mesangial proliferation. Host immunoglobulin was present within the mesangium and along capillary loops in all three. Woodchuck hepatitis virus core antigen (WHcAg) was present along capillary loops of two of these animals, one membranous and one mixed, and in the mesangium of all three. Woodchuck hepatitis virus surface antigen (WHsAg) deposition was similar to WHcAg deposition but was only present along capillaries in those animals with mixed nephritis. The remaining three animals had mesangial proliferation. WHsAg and host immunoglobulin deposition were predominately mesangial; WHcAg was not detected. Transmission electron microscopy showed thickening of the capillary loop basement membranes and subepithelial electron-dense deposits in animal one, and deposits in the mesangium in animal six.
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We compared our standard NIH (extended incubation) crossmatch (XM) with antihuman globulin (AHG) and flow cytometry crossmatches (FCXM) and correlated the results with primary cadaveric and retransplant graft survivals. In addition, we treated the XM sera with the reducing reagent dithioerythritol (DTE) to discriminate IgM from IgG immunoglobulin reactivity. For the 166 CsA-Pred-treated primary cadaveric renal allograft recipients the 1-year graft survival rate following an NIH-NEG XM was 81%. NIH-XM-NEG recipients who were also AHG-XM-NEG displayed an 82% 1-year graft survival as well. In contrast, NIH-NEG, but AHG-POS XM primary CAD recipients displayed a significantly reduced graft survival rate of 67%. Treatment of AHG-POS XM sera with DTE-delineated DTE/AHG-NEG and POS crossmatches associated with significantly different graft survivals of 83% and 0%, respectively, for these primary recipients. Flow cytometry XM results did not improve on the AHG-NEG or DTE/AHG-NEG XM primary graft survivals. These results were seen whether testing pre-Tx or historical (Hx) sera. For Re-Tx recipients an AHG-NEG XM resulted in significantly improved graft survival compared with the NIH-XM-NEG results. The overall 1-year graft survival rate for the 70 Re-Tx recipients studied was 64% (following a NEG pre-Tx NIH-XM). Re-Tx recipients with an AHG-NEG XM displayed an improved graft survival compared with NIH-XM-NEG recipients (77% vs. 64%, P less than 0.05) and with AHG-POS recipients (77% vs. 36%, P less than 0.01). However, treatment of Re-Tx, AHG-POS sera with DTE resulted in comparably poor graft survival rates of 31% and 50% for DTE/AHG-NEG and POS crossmatches, respectively. A FCXM did not improve on the results of Re-Tx graft survival following an AHG-NEG XM. These results were obtained whether testing pre-Tx or Hx sera. HLA matching, PRA, and the time the first Tx was lost did not influence the Re-Tx graft survival outcome following an AHG-NEG XM. Therefore, successful primary cadaveric renal allograft survival can be accomplished following either an AHG-NEG XM or an AHG-DTE-NEG XM. Re-Tx graft survival is significantly improved following an AHG-NEG XM. Re-Tx recipients with an AHG-POS XM who are either DTE/AHG-POS or -NEG display reduced graft survivals compared with AHG-NEG Re-Tx recipients.
Black end-stage renal disease patients may present as an immunologically higher-risk group for renal allograft transplantation than white ESRD patients. To test this hypothesis, we correlated graft survivals in 124 black and 241 white cyclosporine-prednisone-treated primary cadaveric renal allograft recipients with pre-Tx nonspecific immune responder status (strong vs. weak immune responders), donor-recipient-specific MLC responsiveness, HLA match, and blood transfusion (BT) history. One-, 2- and 3-year patient survival rates of 95%, 94%, and 94% were identical for both groups. However, the 1-, 2-, 3-year graft survival rates for white recipients of 82%, 79%, and 75% were significantly higher than the 70%, 62%, and 55% rates for black recipients (P less than 0.01 for each, respectively). Pre-Tx nonspecific immune response values for blacks were significantly (P less than 0.01) higher than for whites (38% vs. 28% for active T cell; 1.8 vs. 1.3 for TH:TS ratio; 28,581 c.p.m. vs. 14,870 c.p.m. for spontaneous blastogenesis; and a stimulation index (SI) of 34 vs. 20 for panel mixed lymphocyte culture). Additionally, the specific recipient-donor MLC (SI) for black recipients was significantly greater than the specific recipient-donor MLC for white recipients (MLC SI of 40 vs. 18, P less than 0.01). Blacks present as pre-Tx strong immune responders with a greater frequency than whites (90% vs. 66%, P less than 0.01). Moreover, black strong responders experience a poorer 1-year graft survival than white strong responders (67% vs. 80%, P less than 0.01). Even though the pre-Tx BT histories of white and black ESRD patients studied herein were comparable, the immunoregulatory effect of pre-Tx BT was different in white vs. black patients. A significant reduction in TH:TS ratio was observed when comparing 0 vs. 1-4 pre-Tx white patient BT groups, whereas significant changes in TH:TS ratios were not observed until after comparing 0 vs. greater than or equal to 5 pre-Tx black patient BT groups. HLA matching and pre-Tx BT had no impact on improving the graft survivals of these CsA-Pred-treated white or black recipients. These data, therefore, support the hypothesis that black recipients present as an immunologically higher-risk group than white recipients.
Although the introduction of cyclosporine-prednisone immunosuppression has improved early renal graft survival, chronic rejection remains a major cause of longterm graft dysfunction. This study retrospectively examined 69 cases of chronic rejection among 643 primary renal allograft recipients treated with cyclosporine-prednisone immunosuppression from July 1981 to October 1989. Chronic rejection was defined as a rejection episode diagnosed greater than 90 days posttransplantation with characteristics of progressive nonacute renal function deterioration, confirmed, in most cases, by renal biopsy. This group was compared with an equal-sized matched cohort. Among cadaveric recipients, 61 of 456 patients (13.4%) displayed chronic rejection, whereas among living-related recipients, 8 of 187 patients (4.3%) developed chronic rejection. The average time from the date of transplantation to diagnosis of chronic rejection was 15 +/- 14 months. One- and three-year graft survivals following diagnosis of chronic rejection were 51% (30/59) and 25% (13/51), respectively, compared with the cohort one- and three-year graft survivals of 98% (58/59) and 86% (32/37) at similar periods posttransplantation. HLA mismatch, PRA status, blood transfusion history, lipid levels, cyclosporine trough levels, incidence of prior acute rejection, and initial graft dysfunction were not significantly different between the chronic rejection group and the matched cohort. Hypertension and proteinuria were significantly associated with chronic rejection (P less than 0.001). Of 58 biopsies performed, findings solely consistent with chronic rejection were observed in 9 cases (15%) and "acute upon chronic" rejection in 49 cases (83%). Treatment of acute concomitants improved the renal function in 43% (27/63) by the time of hospital discharge. Nonetheless, at 12 months the incidence of improved renal function eroded to 22% (13/59), suggesting that the benefit was relatively short-lived. Although the overall incidence of chronic rejection in this group of cyclosporine-prednisone-treated patients was lower than previous azathioprine-prednisone cohorts, the clinical presentation and progression of chronic rejection was similar. Additionally, the incidence of chronic rejection within this series was lower among living-related recipients versus cadaveric recipients of donor organs.
Hemorrhagic fever with renal syndrome (HFRS) is a dramatic illness characterized by fever, and variable degrees of circulatory failure, hemorrhage, and renal insufficiency. Hantaviruses are the cause of this syndrome. In its severe form, it is associated with significant mortality. Vascular dysfunction is the key physiologic derangement in this disorder. There is a growing body of evidence that suggests that immune mechanisms account for this derangement.