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At least 559 records · Page 31Linked to original sources
PubMed1995

Severe or multiple rejection episodes are associated with early recurrence of hepatitis C after orthotopic liver transplantation.

Recurrent hepatitis C causes significant morbidity after liver transplantation. Because immunosuppression is associated with enhanced viral replication, we postulated that clinical recurrence of the disease may be associated with augmented immunosuppression for rejection. In 96 patients with hepatitis C who received liver transplants, we recorded the interval from transplantation to recurrence, the episodes of steroid-resistant rejection (SRR) requiring OKT3, the number of rejection episodes, and the use of OKT3 induction. Recurrence was diagnosed based on elevated transaminases and characteristic histology. Hepatitis C recurred in 43 of 96 patients. Fifteen of 21 patients (71.4%) who previously had SRR had recurrence, versus 28 of 75 patients (37.3%) who either had no SRR (72 patients) or had it after recurrence was diagnosed (3 patients) (P < .01). Mean time to recurrence was 127 +/- 31 days in the 15 patients who had had SRR versus 246 +/- 42 days in the other 28 patients (P = .02). Recurrence and number of rejection episodes were clearly associated: 6 of 33 patients (18.2%) with no rejection had recurrence (P < .05), versus 11 of 26 patients (42.3%) with one rejection episode (P < .05) and 26 of 37 (70.2%) with more than 1 episode (P < .05). OKT3 induction was used in 15 patients; 9 of 15 patients had recurrence (ns) at 337 +/- 95 days. Of 72 patients who initially received triple immunosuppression, 30 patients had recurrence at 186 +/- 25 days (P = .05). Nine patients received primary FK506; 4 had recurrence at 68 +/- 14 days.(ABSTRACT TRUNCATED AT 250 WORDS)

Drug Resistance↗
PubMed1994

Mouse antibody-coated lymphocytes during OKT3 therapy in liver transplantation.

Flow cytometry has been a technique in search of a use in transplantation. With each new monoclonal antibody, it has been hoped that the secrets of rejection would be unlocked. The usefulness of CD3+ T-lymphocyte counts to predict successful treatment of organ transplant rejection has been called into question. CD2+, CD3+, and mouse antibody-coated CD3 lymphocytes were followed by flow cytometry in 44 liver transplant patients during OKT3 therapy for induction or rejection. CD3+ lymphocyte counts did not predict successful management of rejection by OKT3. When expressed as percentages of the total lymphocyte count, an increasing trend in CD2+ and mouse antibody-coated CD3+ lymphocytes after day 7 of OKT3 therapy portended persistent or recurrent rejection within 2 months of treatment. It is uncertain if the increasing population of mouse antibody-coated CD3 cells is due to an immune phenomen or decreased clearance by an ailing liver. Care should be taken when using CD3 lymphocyte counts as indicators of adequate OKT3 therapy in liver transplantation.

Animals↗
PubMed1995

Human p59fyn(T) regulates OKT3-induced calcium influx by a mechanism distinct from PIP2 hydrolysis in Jurkat T cells.

The earliest biochemical event after cross-linking of TCR is the tyrosine phosphorylation of a variety of substrates. At least three nonreceptor tyrosine kinases have been implicated in this signaling cascade: p59fyn(T), p56lck, and ZAP-70. Recently, PLC gamma 1 has been shown to be tyrosine phosphorylated in T cells after receptor activation. This increase in tyrosine phosphorylation correlates with the increased activity of the enzyme. The substrate for PLC gamma 1, phosphatidylinositol 4,5-bisphosphate (PIP2), is hydrolyzed to the protein kinase C activator diacylglycerol and inositol 1,4,5-triphosphate (IP3), which promotes calcium release from the endoplasmic reticulum. These results lend support to the notion that calcium mobilization after TCR cross-linking is mediated by increased levels of IP3. In this study we have cloned and transfected a human p59fyn(T) cDNA in the anti-sense configuration into the human T cell line, Jurkat, resulting in decreased expression of the protein. We find that cell lines expressing significantly reduced levels of p59fyn(T) exhibit significantly lower calcium influx following OKT3 activation. However, the level of IP3 production was unchanged and IP1 and IP2 levels were elevated. These data indicate that p59fyn(T) can regulate calcium influx by a mechanism distinct from PIP2 hydrolysis.

Amino Acid Sequence↗
PubMed1994

Humanization of the murine anti-human CD3 monoclonal antibody OKT3.

OKT3 is a murine monoclonal antibody which recognizes an epitope on the epsilon-subunit within the human CD3 complex. OKT3 possesses potent immunosuppressive properties in vivo and has been proven effective in the treatment of renal, heart and liver allograft rejection. Despite its efficacy, significant problems remain associated with OKT3 therapy, i.e. T-cell activation and the anti-murine antibody response. To address the problem of the anti-murine antibody response we have constructed humanized versions of OKT3. One of the humanized derivatives, gOKT3-7 incorporating the OKT3 complementarity determining regions plus a small number of alterations to the human framework, has an affinity of 1.4 x 10(9) M-1 compared with 1.2 x 10(9) M-1 for the murine OKT3. A humanized antibody (gOKT3-1) incorporating only the CDRs from OKT3 was found to be functionally inactive, confirming the requirement for nonCDR substitutions. gOKT3-7 retains the ability of mOKT3 to induce T cell proliferation in vitro and appears to be a good candidate for further development for in vivo therapy.

Amino Acid Sequence↗
PubMed1994

Pneumocystis carinii pneumonia after liver transplantation in adults.

Proven Pneumocystis carinii pneumonia (PCP) occurred in 8 (5.2%) of 154 adult liver transplant recipients between January 1986 and December 1992. The interval between transplantation and PCP ranged from 69 to 131 days with a mean of 95 days (SD 20 days). The PaO2 breathing room air at diagnosis ranged from 40 mmHg to 75 mmHg with a mean of 59.6 mmhg (SD 13 mmHg). Bronchial washings taken at bronchoscopy stained positively for Pneumocystis carinii and confirmed the diagnosis. Transbronchial biopsy was unnecessary for diagnosis. One patient died from PCP while the remainder recovered. Patients transplanted immediately before the index patients served as controls. Patients who developed PCP had more episodes of rejection (p < 0.05), received more OKT3 (p < 0.05), and were receiving more prednisone (p < 0.05) than controls. They also had lower levels of albumin (p < 0.01), and higher levels of alkaline phosphatase (p < 0.05), alanine (p < 0.01), and aspartate aminotransferase (p < 0.001), and gamma-glutamyltranspeptidase (p < 0.02). This study raises the possibility of selecting patients at risk of PCP for chemoprophylaxis.

Adult↗
PubMed1994

The effect of rabbit antithymocyte serum (RATS) and OKT3 on peripheral blood mononuclear cell subsets following renal transplantation.

Fifty-five renal transplant recipients were studied prospectively for changes in monoclonal antibody-defined mononuclear cell subsets (MCS) over the first 45 days posttransplant. Patients received induction immunotherapy with either monoclonal OKT2(n = 29) or polyclonal RATS (n = 26) preparation. Sequential examinations showed characteristic patterns of MCS depletion, which differed according to the type of therapy received and which subset was examined. In general, induction therapy with RATS resulted in greater and more sustained reduction of most MCS than was seen with OKT3 therapy. In recipients who received OKT3 induction there was a correlation between allograft rejection and an increase in lymphocytes expressing pan-T cell markers and in natural-killer cells. In contrast, rejection episodes in patients receiving RATS were associated with increases in subpopulations of T cells including helper, inducer and suppressor/cytotoxic T-cell subsets. There was no correlation of rejection with B cells or T-cell activation markers. The different patterns of MCS depletion with different antilymphocyte preparations and the association between changes in different MCS and rejection warrant further investigation.

Animals↗
PubMed1995

Effect of OKT3 in steroid-resistant renal transplant rejection.

Between January 1, 1982, and November 1, 1986, 169 cadaver renal graft transplantations were performed at this hospital with CsA as induction therapy. OKT3 was not available in this period. Of these grafts, 15.9% were lost within 6 months, 10.7% from acute rejection (AR). Between November 1, 1986, and October 1, 1992, 483 cadaver renal graft transplantation were performed. Induction therapy included CsA and OKT3 was available. Of these grafts, 8.7% were lost inside 6 months, 3.1% from AR. Of these last 483 grafts, 113 received 125 courses of OKT3. Ten courses were prophylactic, and 115 courses in 103 patients were for rejection resistant to steroid therapy (biopsy proven in all but 2 cases. Ninety-three percent of rejection episodes treated with OKT3 responded, at least initially. Graft survival in OKT3-treated patients was 81%, 77%, and 76% at 6 months, 1 year, and 2 years, respectively. In contrast, graft survival in steroid-resistant rejection during the first period (without OKT3) was 59%, 57%, and 57% at these intervals. There were 8 infective deaths within 6 months in the 113 OKT3-treated patients, compared with 2 in the 343 who did not receive OKT3 (P < 0.001). There were 7 viral deaths in the OKT3 group compared with none in those not receiving OKT3 (P < 0.001). Prophylaxis with oral acyclovir and cotrimoxazole was instituted in October 1990 in OKT3-treated patients and ganciclovir use was increased. Since this change, no further viral deaths have occurred. OKT3 is a very effective antirejection agent, but its use is associated with an increased mortality from viral infections. With appropriate prophylaxis and treatment, however, this mortality can be reduced.

Cyclosporine↗
PubMed1995

Evidence demonstrating poor kidney graft survival when acute rejections are associated with IgG donor-specific lymphocytotoxin.

The current prospective investigation was conducted to determine whether development of IgG donor-specific lymphocytotoxins detected at the onset of acute rejections was predictive of a poor-prognosis acute rejection. Between January 1990 and August 1993, 206 kidney transplants were performed. Cadaver kidney recipients were managed with antilymphocyte globulin as induction therapy and all recipients (i.e., cadaver and living related donor kidneys) received triple immunosuppressive therapy, i.e., CsA, AZA, and prednisone. Rejections were treated with intravenous Solu-Medrol and OKT3. Presence of donor-specific IgG lymphocytotoxin was detected by using dithiothreitol-pretreated sera (obtained at onset of rejection) and frozen donor cells. In addition, percentage of panel reactive antibody was determined on this dithiothreitol-pretreated sera. Of the 82 patients with biopsy-proven acute rejections, 19 were found to have developed donor-specific IgG lymphocytotoxin and a marked increase in panel reactive antibody. One-year graft survival in this group was dismal (16%), despite OKT3 therapy. Over 90% of these patients lost their graft within 2 months of rejection diagnosis. In 63 recipients who had acute rejections without development of IgG anti-HLA antibody, 1-year graft survival was 72%. The majority of these patients lost their grafts from chronic rejection. No anti-HLA activity was found in patients who did not have rejection episodes. Based on this study, evidence indicates that assaying for IgG donor-specific antibody at time of rejection is a valuable tool for selecting a subset of patients with poor-prognosis acute rejections. Identifying this subset will become important as we enter an era of new immunosuppressive agents.

Adolescent↗