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PubMedDate not supplied

Treatment of recurrent heart rejection with mycophenolate mofetil (RS-61443): initial clinical experience.

Mycophenolate mofetil (RS-61443), a derivative of mycophenolic acid, is a new immunosuppressive agent that inhibits de novo purine synthesis in activated lymphocytes. In a clinical trial of mycophenolate mofetil in the treatment of recurrent or persistent heart rejection, 17 patients 0.6 to 104 months (median 5.4 months) after transplantation received a daily oral dose of mycophenolate mofetil of 3000 mg, with seven patients increasing to 3500 mg daily. Azathioprine was routinely discontinued at the start of mycophenolate mofetil treatment. One patient in shock from acute rejection required retransplantation before starting mycophenolate mofetil and died 68 days later of cytomegalovirus sepsis. Another patient died 72 days after mycophenolate mofetil of protracted multisystem failure (present before mycophenolate mofetil). One patient required early cessation of mycophenolate mofetil, and the other 14 patients were alive and well 5 to 10 months after initiating mycophenolate mofetil treatment. Three patients required transient dose reduction and one patient required discontinuation of mycophenolate mofetil because of nausea, diarrhea, or abdominal cramps. No other clinical side effects were noted. Frequency of rejection decreased from 0.67 rejection episodes per patient per month before mycophenolate mofetil to 0.27 rejection episodes per patient per month after mycophenolate mofetil (p < 0.0001). Frequency of infection was unchanged after mycophenolate mofetil (p = 0.9). Renal function was not affected by mycophenolate mofetil (creatinine clearance 1.8 mg/dl before mycophenolate mofetil vs 1.7 mg/dl after mycophenolate mofetil; p = 0.03).(ABSTRACT TRUNCATED AT 250 WORDS)

Administration, Oral↗
PubMedDate not supplied

Efficacy of OKT3 therapy for acute rejection in isolated lung transplantation.

The purpose of this study was to evaluate the efficacy of muromonal-CD3 (Orthoclone OKT3) in the treatment of acute lung rejection. Criteria for its administration were (1) steroid-resistant acute rejection, (2) first-line therapy for grade III or higher acute rejection, and (3) second relapse after tapering off steroid treatment of acute rejection. During the period between May 1990 and May 1992, 41 patients had a total of 101 episodes of acute rejection. OKT3 (5 mg/kg for 7 to 10 days) was administered to 28 patients, of whom 19 responded (68%). Nine patients had either nonresponsive episodes or relapses immediately after completion of OKT3 therapy. Age, gender, cytomegalovirus status, underlying diseases, and type of procedure did not influence the outcome. Timing of OKT3 administration, however, was important; 16 (89%) of 18 patients responded to OKT3 therapy when administered during the first 6 months after transplantation, whereas 3 (30%) of 10 patients responded only beyond 6 months (p < 0.01). Infectious complications occurred after six treatments (21%), in which high-dose steroids were used concurrently (three Aspergillus, two Pseudomonas, and one cytomegalovirus pneumonia). Two patients also taking high-dose steroids had lymphoproliferative disorders. Three allergic reactions developed: one case of edema, one case of hypotension, and one case of arthralgia-myalgia syndrome. Serum antibody titers against OKT3 were persistently negative despite repeat (up to four times) therapy. We conclude that OKT3 is an effective and relatively safe therapy for steroid-resistant, high-grade, or relapsing acute lung rejection during the first 6 months. Antimicrobial prophylaxis must be considered when OKT3 is administered.

Acute Disease↗
PubMed1994

Acute rejection episodes--best predictor of long-term primary cadaveric renal transplant survival.

Uniformly high 1-year primary cadaveric renal transplant survival has prompted an interest in establishing clinical factors associated with longer-term (i.e., more than 5-year) graft survival. We have studied 665 consecutive primary transplanted cadaveric kidneys using sequential quadruple immunosuppression with at least 1 year of follow-up (average 41.4 months). No attempt at HLA matching was made and all rejection episodes were confirmed by histology. Overall, 8-year patient and graft survival were 78% and 60%, respectively. Death as a cause of graft loss occurred in 103 patients. However, only 14 patients died from complications of immunosuppression. A multivariate analysis was performed using age, sex, blood type, race, presence of diabetes, HLA mismatch, current and maximum panel reactive antibody (PRA), time to first rejection episode, treatment of first rejection episode, and number of rejection episodes (none, one, or more than one). Number of rejection episodes was by far the most important co-variate (p = < 0.00001). In total, 53% of patients had no rejection episodes, 25% had one, and 22% had more than one. The occurrence of acute rejection did not correlate with the degree of HLA mismatch or PRA. Demographic and immunologic variables were similar for all three groups. Actuarial 8-year graft survival was negatively affected by rejection history (Fig. 1). Uncensored T1/2 in the group with no rejection episodes was 16.9 years, compared with 3.9 years in the group that experienced more than one such episode.(ABSTRACT TRUNCATED AT 250 WORDS)

Acute Disease↗
PubMedDate not supplied

Signal requirement for induction of MHC-unrestricted antitumor cytotoxicity of human T cell CD4+/CD8+ subpopulations.

The role of cosignalling in the generation of MHC-unrestricted cytotoxicity of T cells was studied with CD4+ and CD8+ sub-populations highly purified (> 98%) by immunomagnetic cell sorting using OKT4 mab, Dynal anti-CD4 mab, OKT8 mab, Dynal anti-CD8 mab, and OKT3 mab. Cytotoxicity was determined in 4 h cytotoxicity assays against K562 tumor cells known to lack expression of MHC class 1 and class 2 antigens, thus avoiding interference with anti-CD4- or anti-CD8-mediated signalling. Signal transfer was induced via CD4, CD8, CD3, IL-2 receptor and RG receptor specifically interacting with a plant rhamnogalacturonan (RG). In CD8+ cells, the first signal delivered by the sorting mab (immobilized OKT8 or Dynal anti-CD8 or OKT3) only induced low MHC-unrestricted cytotoxicity but committed the cells to develop largely enhanced cytolytic potential upon stimulation with a second (IL-2 or RG) or third (OKT3, IL-2, RG) signal. The highest cytolytic potential was achieved by cumulative signalling via CD8, CD3, IL-2 receptor and RG receptor. The generation of MHC-unrestricted cytotoxicity of CD8+ cells correlated with increased effector cell/target cell conjugate formation. In CD4+ cells, OKT4 as sorting mab induced very low cytolytic potential, and a moderate committment to IL-2 signals but a stronger one to RG signals, yielding further cytotoxicity enhancement. The highest cytolytic potential was obtained by cumulative signalling via CD4, IL-2 receptor and RG receptor. Dynal anti-CD4 mab was inefficient and OKT3, as sorting mab of CD4+ cells from CD8-depleted PNAC, appeared to block subsequent OKT4-induced generation of MHC-unrestricted cytotoxicity by delivering a negative signal. Immobilized OKT3 as second signal present in cultures of OKT4-sorted CD4+ cells was inefficient. Surprisingly, soluble OKT3 together with IL-2 delivered a positive signal in cultures of OKT4-sorted CD4+ cells.

CD4 Antigens↗
PubMed1994

Risk factors for invasive fungal infections complicating orthotopic liver transplantation.

Risk factors for invasive fungal infection in patients undergoing orthotopic liver transplantation were examined. Thirty-four of 168 transplants were complicated within 100 days after transplantation by documented invasive fungal infection (Candida species, 28 patients; mycelial fungi, 5; both Candida and Aspergillus species, 1). In the multivariate Cox proportional hazards model, three baseline and two posttransplant variables were independently significant risk factors for infection: level of creatinine (hazard ratio = 1.4), length of transplant operation (HR = 1.2), retransplantation (HR = 3.2), abdominal or intrathoracic reoperations (HR = 2.5), and cytomegalovirus infection (HR = 8.5). Four predictors (creatinine of > 3.0 mg/dL, operative time of > or = 11 h, retransplantation, and early colonization) assessable at the time of transplantation or shortly thereafter were incorporated into a simple predictive model for risk stratification. The risk of invasive fungal infection ranged from 1% in patients with no predictors to 67% in patients with two or more predictors. Strategies to prevent invasive fungal infections after liver transplantation should be targeted to these high-risk groups.

Adrenal Cortex Hormones↗
PubMedDate not supplied

In vivo T cell activation properties of anti-T cell monoclonal antibodies.

Murine monoclonal antibodies specifically directed at the CD3 molecular complex are widely used in clinical transplantation. They are potent inhibitors of immune function and may be administered in association with conventional immunosuppressive drugs. However, their use has been complicated by the severe clinical syndrome that invariably follows the first injections of the antibody. We have shown that this reaction relates to transient T cell activation, with production of a cohort cytokines. This in vivo activating effect is unique to anti-CD3 MoAbs. Furthermore, this property is highly monocyte-dependent, engaging Fc receptors, and thus varies according to the isotype of the administered MoAb. Another anti-T cell MoAb such as the BMA031 directed towards monomorphic determinants of the T cell receptor (TCR) does not promote such massive in vivo activation.

Animals↗
PubMed1993

Mechanism of HIV-1 Tat induced inhibition of antigen-specific T cell responsiveness.

HIV-1 Tat has been shown to have an inhibitory effect on the Ag-specific responsiveness of human peripheral T cells. We have previously demonstrated that this retroviral protein binds to and partially inhibits the enzymatic activity of dipeptidyl aminopeptidase type IV (DP IV), also known as CD26, which is expressed on a variety of mammalian tissue, including T lymphocytes. A number of studies have implicated a role for DP IV in the activation of T lymphocytes. By utilizing HIV-1 Tat, as well as ProboroPro, a potent and specific boronic acid analog inhibitor of DP IV, we show here that blocking DP IV partially inactivates Ag and anti-CD3-mediated T cell proliferation. Neither mitogen nor anti-CD2 mediated proliferation of T lymphocytes, however, is impaired by blocking DP IV. The target molecule for the inhibition induced by both compounds was confirmed by the finding that soluble DP IV neutralized the reduced Ag responsiveness. The Ag-specific inhibition could be overcome by the addition of exogenous IL-2, suggesting that blocking or inactivation of DP IV results in a state of anergy, probably by interfering with the delivery or amplification of a signal necessary for IL-2 production. This is further substantiated by the finding that costimulation of human PBMC via the CD28 molecule, which initiates a non-TCR-dependent signaling pathway, overcomes the reduced Ag responsiveness induced by Tat and ProboroPro. The fact that ProboroPro has no impact on stimulation of T cells with PMA and ionomycin implies that blocking DP IV is influencing events before the activation of protein kinase C and Ca2+ flux. These results suggest that DP IV is necessary for amplification of signals generated by the engagement of the TCR-CD3 complex by nominal Ag.

Adult↗
PubMed1993

In vitro stimulation of human peripheral blood B cells from normal individuals by activated T cells increases the efficiency of hybridoma generation.

Peripheral blood B cells from normal individuals have been less than ideal as a resource for "fusible" cells for the generation of human hybridoma antibodies. In vitro stimulation of normal peripheral blood B cells by CD4+ T cells (HUT 78) that had been activated by a solid phase anti-CD3 monoclonal antibody (OKT3) was investigated to see if differentiation of B cells would result in an increased pool of B cells that could be immortalized. A comparison of the rate of successful fusion, an estimation of the frequency of the fusible cells from the input peripheral blood, and the amount of immunoglobulin secreted both in vitro, prior to fusion, and by the resulting clones in two different in vitro immunization protocols, with and without activated T cells indicated that inclusion of the activated T cells provided the necessary help to drive the B cells to a fusible state. Stimulation by activated T cells improves the efficiency of generating B cell hybrid clones from peripheral blood 10-fold compared to in vitro immunization with antigen alone.

Antibodies, Viral↗
PubMed1993

Interferon-gamma-induced intercellular adhesion molecule-1: expression on human tumor cells enhances bifunctional antibody-mediated lysis through a lymphocyte function-associated antigen-1 dependent mechanism.

Antitumor x anti-CD3 bifunctional antibodies (BFAs) affect tumor cell lysis by activating and physically linking T-cells and tumor cells. Since tumor target antigen expression does not correlate with susceptibility to BFA-mediated tumor cytotoxicity, we investigated the role of cell adhesion molecules as accessory molecules. In 3 human colon tumor cell lines (LS174T, WIDR, and COLO205), recombinant interferon-gamma (rIFN-gamma) consistently increased BFA-mediated tumor cell lysis by cultured peripheral blood lymphocytes and consistently increased tumor cell expression of intercellular adhesion molecule-1 (ICAM-1). Using cell conjugation assays, we demonstrated that ICAM-1 and lymphocyte function-associated antigen-1 (LFA-1) interactions were important for effector-to-target cell conjugate formation and demonstrated that tumor cell pretreatment with rIFN-gamma enhanced cell conjugate formation. Whereas anti-LFA-1 blocked all BFA-mediated tumor lysis and conjugate formation, anti-ICAM-1 blocked only the enhancing effects of rIFN-gamma for both cytolysis and conjugate formation. Although BFAs were shown to provide effector-to-target cell bridging, LFA-1 was found to be a common critical element required for BFA-mediated cell conjugation and lysis. ICAM-1, which was augmented by rIFN-gamma, appears to be only one of several ligands interacting with LFA-1. These results provide one explanation as to why high expression of tumor-associated antigen alone does not predict the susceptibility to BFA-mediated lysis and provides further support for the concept of combined modality immune therapies.

Antibodies, Bispecific↗
PubMed1993

Ganglioside (GM1) distinguishes the effects of CD4 on signal transduction through the TCR/CD3 complex in human lymphocytes.

Ganglioside (GM1) modulation of CD4 off the surface of T lymphocytes defined functions of the CD4 molecule during signal transduction through the T cell receptor (TCR)/CD3 complex. Antibody cross-linking of CD3 alone (3 x 3) stimulated phospholipase C (PLC) activity, rapid Ca2+ flux, and protein phosphorylations in freshly isolated human T lymphocytes. Antibody cross-linking of CD4 and CD3 (3 x 4) stimulated greater signaling than that caused by 3 x 3. Cross-linking CD4 alone did not stimulate these signaling processes. GM1-modulation of CD4 from the cell surface blocked all aspects of the augmented signaling imparted by CD4 co-modulation with CD3. In comparison, pretreatment with the protein tyrosine kinase inhibitor genistein inhibited 3 x 4-stimulated PLC activity and protein phosphorylation but not Ca2+ flux. Antibody cross-linking of the tyrosine phosphatase CD45 with 3 x 4 (3 x 4 x 45) also inhibited CD4-augmented phosphorylations and like genistein did not reduce Ca2+ levels. In conclusion, these data demonstrate that CD4 can augment signal transduction through the TCR/CD3 complex by its physical proximity to CD3. TCR/CD3-signaling augmentation by CD4 stimulated protein tyrosine kinases and PLC activities but stimulated intracellular Ca2+ flux through an independent mechanism(s).

CD4 Antigens↗
PubMed1994

The effects of oral pentoxifylline on the cytokine release syndrome during inductive OKT3.

The cytokine release syndrome (CRS) accompanying OKT3 therapy is a major cause of posttransplant morbidity. The pathogenesis of this syndrome has been attributed to the synthesis of tumor necrosis factor, interleukin 2 (IL-2), interleukin 6 (IL-6), and gamma-interferon in response on T lymphocyte stimulation by OKT3. The hemorrheologic agent pentoxifylline (PTX) inhibits the synthesis of TNF alpha in vitro in response to a variety of stimuli, including OKT3. We performed a randomized, double-blinded trial of PTX during OKT3 induction in recipients of cadaveric renal allografts. Patients received either PTX 800 mg or placebo 2 hr before the initial dose of OKT3 and every 8 hr thereafter during the first 3 posttransplant days. Serum TNF alpha and IL-6 concentrations were measured pre-OKT3 and at 2 and 6 hr post-OKT3 on the first 3 posttransplant days. Despite the achievement of apparently adequate plasma levels of PTX and its active metabolites, no difference was observed in the incidence or severity of clinical manifestations of CRS. Serious manifestations of CRS--including acute pulmonary edema, encephalopathy, and aseptic meningitis--were not seen in either group. Serum TNF alpha and IL-6 concentrations were similar in PTX and control patients throughout the course of the study. Plasma levels of PTX and its active metabolites did not correlate with serum TNF alpha levels, serum IL-6 levels, or the incidence and severity of clinical manifestations of CRS.

Adult↗