E. S. Woodle

Phase I trial of a humanized, Fc receptor nonbinding OKT3 antibody, huOKT3gamma1(Ala-Ala) in the treatment of acute renal allograft rejection.

BACKGROUND HuOKT3gamma1(Ala-Ala) is a genetically-engineered derivative of the parental murine OKT3 monoclonal antibody, in which the six complementarity-determining regions have been grafted within a human IgG1 mAb, and whose C(H)2 region has been altered by site-directed mutagenesis to alter FcR-binding activity, thereby eliminating T cell activation properties. This report describes the results of a phase I trial of huOKT3gamma1(Ala-Ala) treatment of acute renal allograft rejection. METHODS Acute renal allograft rejection in kidney and kidney-pancreas transplant recipients was treated with huOKT3gamma1(Ala-Ala). huOKT3gamma1(Ala-Ala) dosing consisted of daily 5- or 10-mg doses adjusted initially to achieve target levels of 1000 ng/ml. RESULTS A total of seven patients, five kidney transplant and two kidney-pancreas transplant recipients, were treated with the monoclonal antibody for first rejection episodes. Corticosteroids (500 mg i.v. Solumedrol) were given 2 hr before the first huOKT3gamma1(Ala-Ala) dose only. Banff classification of treated rejections were the following: grade I, 1 patient, grade IIA, 1 patient, grade IIB, 4 patients, and grade III, 1 patient. Median time from transplant to rejection was 15 days, and median follow up 12 months (range 10-17 months). HuOKT3gamma1(Ala-Ala) therapy was given for 10.1+/-2.5 days, and mean total dose was 76+/-27 mg. Rejection was reversed in five of seven patients, and recurrent rejection was observed in one patient. Serum creatinine values peaked on day 1 of huOKT3gamma1(Ala-Ala) therapy, and thereafter demonstrated a progressive decline. Rejection reversal (return of creatinine to baseline) occurred at a median of 4 days and a mean of 4.1+/-2 days. Renal allograft biopsies obtained during huOKT3gamma1(Ala-Ala) therapy provided evidence of rapid rejection reversal. Patient and graft survival were both 100%. First dose reactions were minimal, and anti-OKT3 antibodies were not detected. Elevations in serum IL-10, but not IL-2 levels were observed after the first huOKT3gamma1(Ala-Ala) dose. Marked reductions in circulating CD2+, CD4+, and CD8+ T cells were observed after the first huOKT3gamma1(Ala-Ala) dose, followed by a slow progressive return of cell counts toward pretreatment values. Pharmacokinetic analysis revealed a half-life of 142+/-32 hr. CONCLUSIONS HuOKT3gamma1(Ala-Ala) possesses the ability to reverse vigorous rejection episodes in kidney and kidney-pancreas transplant recipients, and in comparison to murine OKT3, possesses minimal first dose reactions and does not seem to induce antibodies that bind the OKT3 idiotype. These results support the conduct of additional clinical trials with the huOKT3gamma1(Ala-Ala) antibody.

Incidence and outcome of infection by vancomycin-resistant Enterococcus following orthotopic liver transplantation

Vancomycin-resistant Enterococcus (VRE) has become a significant nosocomial pathogen. For this study, the records of 325 patients who underwent orthotopic liver transplantation (OLT) were reviewed. Thirty-four patients were infected by VRE (incidence of 10.5%, 14% in adults vs. 5% in children, P < 0.01). Common features of patients who developed infections with VRE included previous antibiotic use (25 patients, 15 of whom received vancomycin), co-infection by other pathogens (28 patients), and relaparotomy following OLT (20 patients). Pulmonary and/or renal failure preceded infection by VRE in 11 and 4 adult patients, respectively. Biliary complications were exceedingly common in patients infected by VRE (28 patients) and significantly increased the risk of infection by VRE (21.5% vs. 3.1% for patients without biliary complications, P < 0.0001). Mortality associated with VRE infections was high (56% vs. 19% for patients not infected by VRE, P < 0.0005). The most frequent cause of death was sepsis (16 of 19 patient deaths), often polymicrobial. The high incidence of infection by VRE following OLT, the lack of effective antibiotics for the treatment of VRE, and the association of VRE with patient mortality emphasizes the need to define the risk factors associated with VRE infection. We suggest early surgical intervention to treat complications that may predispose patients to infection by VRE.

Comparison of pancreas transplantation with portal venous and enteric exocrine drainage to the standard technique utilizing bladder drainage of exocrine secretions.

Although bladder drainage of pancreatic exocrine secretions has been reported to decrease morbidity and improve pancreas allograft survival, significant complications remain associated with this technique. Furthermore, this technique requires systemic venous drainage of pancreas allografts. Evidence suggests that portal venous drainage of pancreas grafts prevents hyperinsulinemia and improves lipoprotein composition. This report documents our initial experience with portal venous and enteric exocrine drainage of pancreas allografts (portal/enteric technique) and compares it with the standard technique of systemic venous and bladder exocrine drainage (systemic/bladder technique). Patient and allograft survival, as well as allograft function, were comparable for the two procedures. There were no significant technical complications in this pilot series. Enteric exocrine drainage was associated with a significant reduction in the incidence of acidosis and dehydration when compared with bladder drainage (P<0.005). The portal/enteric technique also avoided reoperation for enteric conversion, as was required by 33% of patients in the systemic/bladder group. The incidence and outcome of allograft rejection were similar for the two techniques. These data suggest that combined pancreas/kidney transplantation with portal venous and enteric exocrine drainage is safe and results in outcomes similar to the standard technique, while eliminating many complications of bladder drainage. These findings should encourage additional studies to determine the consequences of portal venous drainage.

An analysis of hepatic retransplantation in children

BACKGROUND The limited supply of organ donors has led some groups to reconsider the role of retransplantation. Historically, except for children with malignancies, extrahepatic sources of sepsis, or severe irreversible neurologic injuries, our institution has offered all children with failing liver grafts the option of retransplantation regardless of their current severity of illness. The purpose of this study was to examine the outcome of hepatic retransplantation in children in an attempt to identify factors predictive of outcome and to assess the results of our approach to retransplantation. METHODS Between October 1984 and December 1995, 314 children less than 15 years of age underwent a total of 441 liver transplants. Data were obtained retrospectively by review of hospital records. RESULTS With a mean follow-up period of 5.3+/-2.7 years, the overall patient survival rates at 1 and 5 years were 77.1% and 67.1%, respectively. Primary allograft survival rates were 65.6% and 56.5%, respectively. Of the 137 patients who developed failure of their primary allograft, 92 underwent retransplantation (29.3% of all primary transplants). Both patient and allograft survival rates were significantly decreased after retransplantation (P<0.0001 versus primary transplants). Univariate and multivariate analysis of retransplanted patients revealed only two factors that were statistically related to patient and graft survival: age at the time of retransplantation (P<0.02 univariate and P<0.05 multivariate) and retransplantation with a reduced-size allograft (P<0.005 univariate and P<0.05 multivariate). In this series, the effect on patient survival of differences in medical condition as reflected by United Network for Organ Sharing (UNOS) status approached, but did not achieve, significance (P=0.08 for UNOS 1 versus UNOS 2 and 3). UNOS status did not affect graft survival. Neither the cause of primary allograft loss or the timing of retransplantation relative to the first transplant were related to outcome. CONCLUSIONS These data demonstrate that the failure of primary hepatic allografts remains a major problem in pediatric liver transplantation and that the overall results of retransplantation were significantly worse than those associated with primary transplants. We have identified a group of children who experienced a significantly worse outcome after retransplantation. This group consisted of children less than 3 years of age retransplanted using reduced-size grafts. Based on this finding, we now attempt to avoid retransplanting young children with reduced-size grafts. By using this approach, we hope to be able to offer children the option of retransplantation with improved results and simultaneously minimize the negative impact on patients awaiting primary transplants.

Tacrolimus therapy for refractory acute renal allograft rejection : Definition of the histologic response by protocol biopsies

UNLABELLED Protocol biopsies were performed to define the histologic response to tacrolimus therapy in patients with refractory acute renal allograft rejection. Renal allograft biopsies were performed at defined intervals after initiation of tacrolimus therapy. Protocol biopsies were performed before tacrolimus therapy (within 48 hr of initiation of therapy) and after 1 week of therapy. If the 1-week biopsy did not show rejection reversal, repeat protocol biopsies were obtained at 1- to 2-week intervals, until histologic reversal was observed. Additional biopsies were obtained at 4 weeks and at 8-12 weeks after initiation of tacrolimus therapy. Indicated biopsies were also performed to evaluate increases in serum creatinine. A total of 92 biopsies were performed in 23 patients (average 4.0 biopsies/ patient). Biopsies were performed in each patient immediately before starting tacrolimus therapy (23 biopsies), and 69 biopsies (3.0 biopsies/patient) were performed during tacrolimus therapy. Rejection diagnosis was based on strict Banff criteria. Pretacrolimus biopsies demonstrated mild acute rejection in 64% of patients and moderate acute rejection in 36%. One week after initiation of tacrolimus therapy, protocol biopsies revealed the following: no rejection (60%), improvement (13%), no change (20%), and worsening rejection (7%). Histologic changes at 1 week did not correlate with changes in renal function, as 63% of patients that showed histologic improvement or reversal during the first 2 weeks of therapy did not show improvement in serum creatinine. A lack of histologic improvement (or worsening) at 1 week was demonstrated in a significant proportion of patients (27%); increased tacrolimus dosing provided rejection reversal or improvement in 1-2 weeks in each of these patients. Recurrent rejection was diagnosed on eight biopsies in seven patients, however six episodes were diagnosed by protocol biopsies alone (i.e., in the absence of an elevation in serum creatinine). Delayed improvement in renal function, despite histologic reversal, was likely due to physiologic effects of tacrolimus (i.e., afferent arteriolar vasoconstriction), as histologic evidence of tacrolimus toxicity was not observed during the first 2 weeks of therapy. Histologic evidence of tacrolimus nephrotoxicity (nodular arteriolar hyalinosis) was found in 21% (15 of 69) of biopsies in 39% of patients (9 of 23) at a median time of 60 days (range 12-150 days). Tacrolimus dose and blood levels (by IMx assay) did not correlate with development of clinically silent or clinically evident nephrotoxicity. IN CONCLUSION 1) protocol biopsies provide information that allows individualization of tacrolimus rejection therapy, 2) histologic resolution of rejection often precedes biochemical improvement, 3) histologic evidence of tacrolimus nephrotoxicity is seldom observed in the first 2 weeks of therapy, and 4) clinically silent recurrent rejection and clinically silent tacrolimus nephrotoxicity are observed with significant frequency during tacrolimus therapy for refractory renal allograft rejection.

Anti-CD3 monoclonal antibody therapy : an approach toward optimization by in vitro analysis of new anti-CD3 antibodies

Several problems remain associated with anti-CD3 monoclonal antibody therapy, including first-dose reactions, recurrent rejection, and the host humoral response to the xenogeneic mAb. One approach toward optimization of anti-CD3 mAb therapy involves the use of anti-CD3 mAbs of defined idiotype, isotype, and epitope specificity, so that the desired T cell activation and suppression properties are obtained and neutralization by antiidiotypic antibody is avoided. The purpose of the present study was to define the contribution of mAb isotype and epitope specificity in determining T cell activation and suppression potencies and to evaluate the idiotypic relationships among ten anti-CD3 mAbs and one anti-TCR alpha beta mAb selected for this study. Epitope mapping by flow cytofluorometry indicated that one mAb, OKT3D, possesses an epitope specificity distinct from that of other anti-CD3 mAbs. Analysis of early T cell activation, proliferation, and lymphokine production (TNF-alpha, gamma-IFN, and GM-CSF) indicated that mAb isotype exerted a profound effect on activation potency (IgG2a much greater than IgG1 greater than IgG2b), whereas epitope specificity exerted a minor effect. CTL inhibition studies demonstrated an epitope effect with highest inhibition potencies observed with OKT3D IgG1 and OKT3D IgG2b mAbs. Idiotypic analysis of nine mAbs indicated that all anti-CD3 mAbs except OKT3E possess idiotypes distinct from that of OKT3. Thus, two anti-CD3 mAbs, OKT3D IgG1 and OKT3D IgG2b, possess high immune suppression potency, low activation potency, and idiotypes distinct from OKT3. In conclusion, selection of anti-CD3 mAbs of defined idiotype and appropriate T cell activation and suppression properties may provide a means for mitigating problems associated with OKT3 therapy.