Biomedical subjects

R H Kerman

Publications and source records attributed to R H Kerman.

At least 19 recordsLinked to original sources

PubMed1992

1,25-Dihydroxyvitamin D3 enhances the generation of nonspecific suppressor cells while inhibiting the induction of cytotoxic cells in a human MLR.

The active vitamin D metabolite, 1,25-dihydroxyvitamin D3 (1,25-D3), has been shown in both in vitro and in vivo experiments to be immunoregulatory. We analyzed the effects of the hormone on the human mixed lymphocyte reaction (MLR), the in vitro model of allograft response. Suppressor-cell activity of MLR-generated effector cells was enhanced by calcitriol (10(-10) to 10(-8) M). This suppressor activity was nonspecific since calcitriol-generated effector cells could suppress a primary MLR with stimulators and/or responders heterologous to the effector-generating MLR. Calcitriol (10(-9) to 10(-7) M) was also effective in preventing the generation of cytotoxic T cells when tested in a 51Cr release assay. While no differences were observed in the phenotypic analyses of the MLR-generated effector cells between 1,25-D3-treated cells and control cells, a significant reduction of class II antigen expression was observed in the presence of the hormone. The effects of calcitriol on human MLR are similar to those observed with cyclosporine.

Calcitriol↗

PubMed1992

Influence of race on crossmatch outcome and recipient eligibility for transplantation.

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.

Black People↗

PubMed1991

AHG and DTE/AHG procedure identification of crossmatch-appropriate donor-recipient pairings that result in improved graft survival.

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.

Cyclosporins↗

PubMed1991

Possible contribution of pretransplant immune responder status to renal allograft survival differences of black versus white 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.

Black People↗

PubMed1991

Chronic rejection in primary renal allograft recipients under cyclosporine-prednisone immunosuppressive therapy.

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.

Blood Transfusion↗

PubMed1991

Production of synergistic but nonidentical mechanisms of immunosuppression by rapamycin and cyclosporine.

We report that the mechanism of rapamycin (RAP) inhibition is synergistic, but nonidentical, to the mechanism of CsA inhibition. Like CsA, RAP inhibits T cell proliferation following mitogen (PHA) and/or alloantigen (MLR) stimulation. RAP levels of 100, 33, 11, 3.6, 1.2, and less than 1 ng/ml reduced PHA stimulation by 81%, 84%, 81%, 83%, 62%, and 33%, respectively, without cytotoxicity. The RAP concentration required to achieve 50% proliferative inhibition of either mitogen (PHA) or MLR assays revealed an interindividual variability of 5 pg/ml RAP (2 individuals), 1 ng/ml (3 individuals), and 100 ng/ml (2 individuals). Unlike CsA, RAP proliferative inhibition was not restricted to the G0 phase of the cell cycle. Addition of 100, 10, or 1 ng/ml RAP at the onset (G0), or 24 hr following cultivation (G1) similarly inhibited DNA synthesis by 42%, 42%, and 41% compared with 44%, 48%, and 47%, respectively. PWM-stimulated B cell proliferation was primarily RAP-sensitive during the G0 phase of the cell cycle. RAP at 100, 10, and 1 ng/ml inhibited B cell proliferation 46%, 51%, and 50% when added during G0 but only 15%, 20%, and 20% when added during G1. Generation of a cyclosporine-sensitive cytoplasmic activation signal, activator of DNA replication (ADR), was reduced by RAP. RAP reduction did not correlate directly with T cell proliferative inhibition (as does CsA). RAP-induced proliferative inhibition of 40% and 80% resulted in ADR inhibition of 16% and 33%. Proliferative inhibition was synergistically increased when CsA and RAP were used in combination, whereas ADR inhibition was only additively enhanced. Mechanistic disparity between RAP and CsA may potentiate clinical immunosuppression when RAP and CsA are used together.

B-Lymphocytes↗

PubMed1991

Failure of prolyl-peptidyl isomerase to mediate cyclosporine suppression of intracellular activation signal generation.

Cyclosporine blocks the generation of a cytoplasmic activation protein, activator of DNA replication (ADR). The recent demonstration that cyclophilin is a CsA-sensitive prolyl-peptidyl-isomerase (PPIase), has prompted speculation that CsA immunosuppression is mediated by PPIase interaction with activation signals like ADR. We report that PPIase converts ADR from an inactive to an active form, but the interaction is resistant to CsA. ADR is a sensitive marker of CsA immunosuppression. ADR, extracted from the cytoplasm of PBLs stimulated with PHA, is not detectable in the cytoplasm of resting cells. ADR is quantitated by measuring uptake of 3H/thymidine triphosphate (3H/TPP) into isolated nuclei as a measure of DNA synthesis. The CsA-induced reduction of ADR content mirrored CsA-induced proliferative inhibition in intact cells. CsA concentrations of 1.5, 3, or 4.5 mM reduced T cell proliferation by 26%, 47%, and 58%, and ADR content by 32%, 45%, and 53%, respectively. The ability of PPIase to catalyze the transition of ADR between active and inactive forms was determined by measuring changes in DNA synthesis when 1 microgram/ml PPIase was added to (1) isolated nuclei, (2) nuclei plus ADR, and (3) nuclei plus the cytoplasmic fraction from resting cells. DNA synthesis in isolated nuclei (899 +/- 45 cpm) was unchanged by PPIase (1009 +/- 221 cpm). Addition of PPIase to ADR from activated cells marginally reduced ADR's capacity to trigger 3HTTP incorporation into isolated nuclei (ADR, 4113 +/- 106 cpm; PPIase-treated ADR, 3198 +/- 453 cpm), showing that PPIase cannot reduce ADR activity. However, treatment of resting cell cytoplasm with PPIase increased ADR activity 5-fold (899 +/- 46 vs. 5035 +/- 75 cpm). Addition of 1.5 or 3 mM CsA to resting cytoplasm, primed with PPIase (5035 +/- 75 cpm), resulted in 3HTPP incorporation of 6575 +/- 152 and 5076 +/- 168 cpm, respectively. Thus, PPIase activation of ADR is CsA-resistant. Furthermore, PPIase could not reverse CsA-induced inhibition of ADR. CsA (3 mM) treatment of PHA-stimulated cells rendered proliferation by 30% and ADR by 35%. ADR isolated from cells treated with CsA (9110 +/- 750 cpm) was not increased by treatment with PPIase (9185 +/- 449 cpm). These findings suggest that PPIase converts ADR from an inactive to an active form. However, the mechanism of CsA inhibition of ADR is neither mediated nor overridden by PPIase.

Amino Acid Isomerases↗

PubMed1991

Preemptive transplantation--an analysis of benefits and hazards in 85 cases.

The benefit of transplantation without prior dialysis might be contravened by the failure to develop possible immunologic disabilities associated with chronic uremia and dialysis. This study compares graft and patient outcome, cyclosporine toxicity, pharmacokinetics, rejection episodes, nutritional status, and social and vocational rehabilitation between a preemptive group of 85 patients transplanted without prior dialysis and a cohort of 84 demographically, temporally, and disease-matched recipients of renal transplants after a minimum of 6 months' chronic dialysis therapy. The groups were matched for donor type, gender, and age, as well as immunologic risk factors of HLA-mismatch and percent panel-reactive antibody. All patients received CsA and prednisone immunosuppression. There were only two differences between the cohorts. The preemptive group included more diabetic patients: 32 versus 15 (P less than 0.01). The control cohort included more recipients who had received any pretransplant transfusion: 55 versus 28 (P less than 0.001). Both of these factors (if having any impact) would be expected to reduce graft survival in the preemptive group. All patients in the study had a minimum follow-up of 1 year and over half of the recipients are beyond 40 months. The preemptive patients showed survival rates of 94, 93, and 91 percent at 1, 2, and 5 years. These rates were not significantly different from those of the control group, namely 96, 96, and 93 percent, respectively. The actuarial graft survival rates in the preemptive group of 83, 81, 76, 73, and 73 percent at 1, 2, 3, 4, and 5 years were not statistically different from the control group rates, namely 90, 81, 80, 77, and 76 percent. Preoperative blood transfusion or percent positive panel-reactive antibodies had no effect on postoperative outcome in either group. The incidence of CsA nephrotoxicity was 9.4 percent in the preemptive group, which was not statistically different from the 17.9 percent in the control group. The incidence of rejection episodes in the absence of patient noncompliance was comparable between the groups. Seven of the irreversible rejection episodes in the preemptive group were due to noncompliance, compared with none in the control group (P less than 0.001). Preemptive recipients were also more likely than control group patients to be employed fulltime both before transplantation (36 vs. 22, P less than 0.05) as well as after transplantation (38 vs. 20, P less than 0.01).(ABSTRACT TRUNCATED AT 400 WORDS)

Biological Availability↗

PubMed1991