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PubMed1996

Interim monitoring of longitudinal comparative studies with recurrent event responses.

A method of interim monitoring is described for longitudinal comparative studies in which the outcome of interest is a recurrent event and treatment comparisons are based on expected numbers of events. The nonparametric methods described by Cook, Lawless, and Nadeau (1996, Biometrics 52, 116-130) are generalized to provide a robust estimate of the covariance matrix for a sequence of test statistics calculated over time. The error spending function methodology of Lan and DeMets (1983, Biometrika 70, 659-663) is adopted to control the experimental type I error rate. A simulation study indicates satisfactory frequency properties of this procedure for the moderate to large scale trials for which it is intended. Extensions of this approach to handle stratified designs and studies with multitype recurrent events are indicated. Data from a kidney transplant study (Cole et al., 1994, Transplantation 57, 60-67) are used for illustrative purposes.

Antilymphocyte Serum↗
PubMed1996

T10B9 (MEDI-500) mediated immunosuppression: studies on the mechanism of action.

The murine IgM anti-human CD3/TCR mAb T10B9 is an effective agent for the reversal of acute cellular renal allograft rejection which offers several advantages over conventional OKT3 therapy. These include reduced morbidity and a more rapid decrease in serum creatinine levels. In the studies presented here comparing T10B9 and OKT3, soluble T10B9 is shown to be a nonactivating anti-T cell mAb. Evidence for its lack of activating potential includes in vitro failure to stimulate PBMC proliferation either alone or in the presence of nonmitogenic doses of phorbol ester, failure to induce the expression of early and late activation antigens and failure to induce IFN-gamma, TNF-alpha, IL-6 or IL-2 release. Analysis of acute renal allograft rejection patient plasma cytokine levels 2 h after the first dose support the hypothesis that T10B9 has reduced immunoactivation activity in vivo. Both TNF alpha and IFN gamma patient plasma levels are significantly reduced in T10B9 as compared to OKT3 therapy. However, T10B9 is capable of cellular signaling as demonstrated by its ability to induce apoptosis and IL-2 release in the human T cell line Sup-T13. Thus T10B9 retains the potent immunosuppressive activity of OKT3 with reduced immunoactivation.

Antibodies, Monoclonal↗
PubMed1996

OKT3 induction therapy: influence of duration on rejections and infections.

Anti-lymphocytes induction therapy in renal transplants remains controversial relative to efficacy and cost benefit. It has been suggested that shortening the duration of induction therapy from 14 to 7 d would provide adequate efficacy at less cost. Our objective was to compare the efficacy and complications of short (7 d or less, group A) versus standard (14 d or more, group B) duration of OKT3 induction therapy in renal allograft recipients. We performed a retrospective review of all renal allografts performed between July 1989 and September 1994. Two groups were identified based on the duration of OKT3 induction therapy. There were no significant differences between group A or B in the distribution of age, sex, race, degree of HLA matching, and etiology or renal failure. Patients in group B experienced fewer rejections at 3 and 12 months (p = 0.0236 and p = 0.0065, respectively) as well as fewer viral infections during the first year of follow-up (p = 0.0435). No difference on the mean number of bacterial or fungal infections existed between the two groups. There were no statistically significant differences in patient or graft survival, although patients in group B had a tendency towards increased 1-yr graft survival.

Adolescent↗
PubMed1996

Impact of first acute rejection episode and severity of rejection on cadaveric renal allograft survival.

A total of 504 renal transplants were performed between 1984 and 1993; 408 (81%) were cadaver grafts. This study evaluated the impact of a first acute rejection episode and the severity of the rejection on cadaveric allograft survival. Acute allograft rejection was based on clinical evaluation and confirmed by renal biopsy. Ten patients were excluded from this study due to early patient or graft loss. Patients were divided into Group I (n = 179), who never experienced acute rejection, and Group II (n = 219), who had an acute rejection episode. Group II patients were divided into IIA (n = 140), who had a mild first acute rejection episode treated with methylprednisolone, and IIB (n = 79), who had moderate or severe acute rejection treated with OKT3. The overall 1-, 2-, 3-, and 5-yr actuarial cadaveric renal allograft survival for Group I was 80%, 76%, 74%, and 68%. The corresponding graft survival for Groups IIA and IIB were 75%, 63%, 58%, and 50%; and 79% 71%, 65%, and 53% [p = 0.03 (I vs IIA), p = NS (I vs. IIB and IIA vs IIB)]. A similar pattern of survival was seen in primary kidney allograft recipients. In conclusion, long-term graft survival was superior in patients who never experienced acute rejection compared to those with rejection. Improvements in long-term graft survival can be accomplished in patients with severe rejection with OKT3 treatment resulting in comparable survival to those with mild rejection.

Actuarial Analysis↗
PubMed1997

CD3+ CD8+ CTL activity within the human female reproductive tract: influence of stage of the menstrual cycle and menopause.

The human female reproductive tract (RT) has been analyzed by others with respect to NK cell cytolytic activity, but not CD3+ T cell (CTL) cytolytic activity. Here, we describe the cytolytic capacity of mucosal CD3+ T cells both longitudinally within the RT (Fallopian tube, uterine endometrium, endocervix, ectocervix, and vaginal mucosa) and temporally throughout the menstrual cycle, using a redirected lysis assay system. Cytolysis by CD3+ CD8+ T cells is found throughout the RT and appears to be hormonally regulated, since in the uterine endometrium, the capacity for CD3+ T cell cytolytic activity is present during the proliferative phase of the menstrual cycle and absent during the subsequent secretory (postovulatory) phase. In contrast, in postmenopausal women the entire RT, including the uterus, retains the capacity for strong CD3+ T cell cytolytic activity. These findings suggest that the high levels of estradiol and progesterone present during days 14 to 28 of the menstrual cycle down-regulate CTL activity in the uterus. As a consequence, the absence of this activity may allow implantation of a semiallogeneic embryo that would otherwise be rejected. Further, these studies indicate that CTL activity is regulated differentially in different regions of the RT, persisting in the cervix and vagina throughout the menstrual cycle.

Adult↗
PubMed1997

OKT3 therapy increases cyclosporine blood levels.

Numerous drugs have been reported to alter cyclosporine (CSA) blood levels, most notably, those drugs that interfere with cytochrome P450 metabolism. Our clinical experience suggested that OKT3 therapy may alter CSA blood levels as well. The purpose of this study was to assess the effect of OKT3 therapy on CSA trough blood levels. We reviewed medical records of all CSA-treated renal transplant recipients during a 3-yr period to identify patients who received antilymphocyte induction therapy. Patients receiving drugs known to interact with CSA were excluded from analysis. The study population (n = 33) was divided into two groups: the OKT3 group consisting of 17 patients who received OKT3 therapy for 7 d post-transplant (OKT3 group) and the control consisting of 16 patients who received ALG induction therapy for 7 d post-transplant (ALG group). Oral CSA (14 mg/kg) was administered preoperatively. Postoperatively, oral CSA (4 mg/kg) was administered twice daily, in addition to corticosteroids and azathioprine. We evaluated CSA through levels on days 1, 3, 5, and 7 of antilymphocyte therapy and 3 d following completion of antilymphocyte therapy. On days 1 and 3, CSA trough levels did not differ between the two groups. However, median CSA trough levels (HPLC) were significantly higher among OKT3-treated patients on day 5 of therapy (265 ng/ml), as compared to ALG-treated patients (136 ng/ml; p < 0.0001; Mann-Whitney U-test). On days 7 and 10, CSA trough levels did not differ between the two groups. CSA does, however, had been adjusted based on levels obtained on day 5. We conclude that OKT3 therapy causes a significant rise in CSA trough levels. Recognition of this potential drug interaction is essential in titrating CSA doses in the early post-transplant period to minimize risks of CSA toxicity or early rejection following induction therapy.

Adult↗