Induction immunotherapy in heart transplantation with T10B9.1A-31: a phase I study.

Cytolytic induction therapy of heart transplantation with OKT3 (immunoglobulin G2a isotype, anti CD3 idiotype) or T10B9.1A-31 (immunoglobulin MK isotype, anti-T-cell receptor alpha beta idiotype) was done in an open-label trial to determine the safety and efficacy of the latter monoclonal antibody. A total of nine patients undergoing orthotopic heart transplantation received a 10-day course of either T10B9.1A-31 (T10B9) (n = 4) 18 mg on bypass and 6 mg intravenously every 12 hours or OKT3 (n = 5) 10 mg on cardiopulmonary bypass and 5 mg intravenously daily. Endomyocardial biopsy surveillance revealed no rejection during induction therapy with T10B9, and one OKT3 induction failure was successfully treated with T10B9, all without significant side effects. T10B9 effectively prevented the onset of early acute rejection in heart transplantation with minimal side effects. T10B9 reversed rejection in one patient whose OKT3 induction failed. Results are encouraging and warrant further investigation.

Treatment of renal allograft rejection with T10B9.1A31 or OKT3: final analysis of a phase II clinical trial.

BACKGROUND: Treatment of acute renal allograft rejection with the monoclonal antibody (mAb) OKT3 has been shown to be superior to treatment with polyclonal antisera. To date, only OKT3 has demonstrated consistent efficacy in reversing rejection crisis. METHODS: From 1989 to 1993, a phase II trial comparing the mAb T10B9.1A31 (T10B9) with OKT3 for treatment of acute cellular rejection in renal allograft recipients was done at the University of Kentucky. We collected data from 178 patients potentially eligible to enter the study; 48 never rejected, 9 refused, 13 could not be biopsied, 16 received methylprednisolone, and 11 received antithymocyte globulin or OKT3. Altogether, 81 patients entered the study, 76 of whom were able to be evaluated. Patients with biopsy-confirmed acute rejection were randomly assigned to T10B9 or OKT3 for at least 10 days. RESULTS: Demographically, there was no difference between the T10B9 or OKT3 cohorts. Actuarial graft survival at 4 years was 87% for patients receiving T10B9, 79% for those receiving OKT3, and 89% for those receiving both mAbs (P=0.55). Patient survival at 4 years was 94% for T10B9, 100% for OKT3, and 89% for both mAbs (P=0.45). Mean creatinines of the cohorts were no different at 1, 6, 12, 24, and 36 months. There was less cytokine nephropathy (P<0.001) observed in patients receiving T10B9. Untoward gastrointestinal, neurological, respiratory, and febrile effects were significantly more frequent in the OKT3 cohort after the first dose (day 0) and with later (day 1-9) administration. Cytokine levels (tumor necrosis factor alpha and interferon gamma) measured 2 hr after the first dose were three to six times higher in patients treated with OKT3 than in those treated with T10B9 (P<0.005). Infectious complications were not significantly different, although serious infections occurred only in patients receiving OKT3. No cases of posttransplant lymphoproliferative disorder were seen in either cohort. Human anti-mouse antibody development was as follows: titer 1:100, 30% T10B9, 42% OKT3; titer 1:1000, 3% T10B9, 3% OKT3. There was no cross-reactivity with OKT3 in patients treated with T10B9, and there was only 9.7% cross-reactivity to T10B9 in patients treated with OKT3. CONCLUSIONS: T10B9 provides treatment for renal allograft acute cellular rejection as effective as that of OKT3 with fewer untoward effects, less cytokine release and nephropathy, fewer serious infections, and without increased development of human anti-mouse antibody. The lack of cross-reactivity offers an alternative therapy should the first mAb fail or re-rejection occur. A phase III trial should be initiated in renal allograft recipients, and phase I and phase II trials should be initiated in other solid-organ transplantations.

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.

Acute effects of gentamicin on thick ascending limb function in the rat.

It is well established that the aminoglycoside antibiotics can adversely affect proximal tubule function. Predominantly indirect evidence suggests that aminoglycosides may also affect function of more distal nephron segments. The present study utilized whole kidney clearance, in vivo micropuncture and in vitro microperfusion to directly determine whether acute gentamicin treatment affects sodium chloride transport in the thick ascending limb of the loop of Henle. Gentamicin (25 mg/kg) significantly increased urine flow, as well as sodium, potassium and chloride excretion within 15 min of intravenous injection. Glomerular filtration rate and proximal tubule fluid reabsorption were not altered by acute gentamicin treatment. In contrast, both fractional and absolute loop chloride transport was significantly decreased. In the in vitro microperfused medullary thick ascending limb, luminal but not basolateral administration of gentamicin (1 mM) significantly decreased chloride reabsorption when compared to time controls. These data suggest that the increased urine and electrolyte excretion associated with acute gentamicin treatment is, at least in part, a consequence of decreased transport in the thick ascending limb of Henle's loop.

Phosphate transport in isolated and perfused renal tubules.

In summary, studies of phosphate transport by isolated renal tubules perfused in vitro confirm many of the data obtained by other techniques with regard to localization. The major contributions of the technique revolve around studies of segments not accessible to micropuncture techniques and around studies of epithelial transport processes that are difficult to examine in vivo.