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Biomedical subjects

A B Cosimi

Publications and source records attributed to A B Cosimi.

At least 109 records · Page 6Linked to original sources
PubMed1993

Monoclonal antibodies in organ transplantation.

Monoclonal antibody (mAb) technology has made possible the production of designer proteins, specifically reactive with almost any conceivable biological molecule. Using these reagents, the surface molecules on cells crucial for allograft rejection have been identified and described in detail. These structures can now be selectively targeted by mAb-based therapy in order to prevent rejection. For instance, the CD3 molecule, expressed on all mature T lymphocytes, triggers T cell activation, a key event in rejection. OKT3, an anti-CD3 mAb, disrupts T cell function and is now the agent of choice for the treatment of severe rejection episodes. MAbs targeting other T cell molecules are currently being investigated. Some of the most promising, the anti-CD4, anti-ICAM-1, and anti-interleukin 2 receptor mAbs, have already induced donor-specific tolerance in rodent models. These hosts accept permanently a genetically incompatible graft after only a limited period of mAb therapy. Interestingly, anti-ICAM-1 also diminishes the ischemic injury of preservation. The development of these new molecular agents, effectively directed to specific cellular targets, will likely play an increasingly important role in future clinical protocols, and perhaps finally provide a means to achieve long-term tolerance in human allograft recipients.

Journal Article↗
PubMed1993

Nonhuman primate responses to murine and humanized OKT4A.

A nonhuman primate antimurine response (MAMA) has been observed in 17 cynomolgus renal allograft recipients of murine OKT 4A. Neither cyclosporine, nor total-lymphoid irradiation, nor donor bone marrow preparation inhibited this antixenogeneic response. In an attempt to alter the antimurine basis of the response, a humanized chimeric OKT4A (IgG4) containing the entire variable portion of the murine OKT4A and a humanized CDR grafted OKT4A mAb sharing only the Complementarity Determining Region from the murine OKT4A, were administered to 8 cynomolgus allograft recipients. MAMA was detected in each recipient. In contrast to sera from recipients of murine OKT4A, sera from recipients of humanized OKT4A displayed no reactivity to other murine mAbs. MAMA specificity did not assay constant (C) region differences between the murine and humanized mAb; however, C region homology in humans should preclude a human antimouse antibody (HAMA) to the Fc portion of a humanized mAb. Furthermore, cynomolgus recipient serum levels of the humanized OKT4A mAb were maintained (> 1 microgram/ml) for a longer period than following treatment with murine OKT4A (murine < 12 days versus between 12 and 24 days for the humanized). If the HAMA response to humanized mAb in future clinical trials, were to be predictably anti-idiotypic, then the opportunity for treatment with sequential mAbs of differing idiotypes would be retained. Moreover, these current studies also suggest that humanized construction may influence the duration of therapeutic mAb levels. Thus, anti-idiotypic reactivity may not be as consequential to the clinical administration of humanized mAb to allograft recipients.

Animals↗
PubMed1993

A phase I trial of immunosuppression with anti-ICAM-1 (CD54) mAb in renal allograft recipients.

Several adhesion molecules contribute to the interaction between T cells and antigen presenting cells or target cells. Leukocyte function-associated molecule-1 (LFA-1[CD11a/CD18]) and intercellular adhesion molecule-1 (ICAM-1 [CD54]) are one such critical adhesive receptor-counter-receptor combination. The importance of ICAM-1 dependent adhesion in the rejection response was initially demonstrated in cynomolgus renal allograft recipients treated with the anti-ICAM-1 murine monoclonal antibody BIRR1. BIRR1 also appeared to limit ischemic damage in these animals. A Phase I clinical trial has subsequently been completed in 18 patients who received cadaver donor renal allografts at high risk for delayed graft function (prolonged preservation time, highly-sensitized recipient). An adequate BIRR1 serum level was associated with significantly less delayed graft function (P < .01) and rejection (P < .01). In 1-hr biopsies, mouse IgG was detected along the endothelium of the vessels and glomeruli in the graft. There were no instances of primary non-function (PNF), and current allograft survival (followup: 16-30 months) in these "high-risk" mAb-treated patients is 78%. There were 3 instances of PNF and a graft survival rate of 56% in the recipients of the contralateral kidney allografts treated with conventional immunosuppression. No significant "first-dose" effect was associated with BIRR1 administration. These results establish a dosing schedule and the clinical safety of BIRR1. They also suggest that inhibition of leukocyte adhesion by mAb therapy may be useful in controlling allograft rejection and possibly in limiting reperfusion injury. Thus, these observations support the clinical importance of accessory molecules in T cell function. We hypothesize that anti-CD54 mAb acts by blocking leukocyte adhesion to the endothelium, thereby interfering with sensitization or target cell interaction.

Adolescent↗
PubMed1993

Hepatic retransplantation in New England--a regional experience and survival model.

Hepatic retransplantation (reTx) offers the only alternative to death for patients who have failed primary hepatic transplantation (PTx). Assuming a finite number of donor organs, reTx also denies the chance of survival for some patients awaiting PTx. The impact of reTx on overall survival (i.e., the survival of all candidates for transplantation) must therefore be clarified. Between 1983 and 1991, 651 patients from the New England Organ Bank underwent liver transplantation, and 73 reTx were performed in 71 patients (11% reTx rate). The 1-year actuarial survival for reTx (48%) was significantly less than for PTx (70%, P < 0.05). This survival varied, dependent on the interval of time following PTx in which the reTx was performed (0-3 days, 57% survival; 4-30 days, 24%; 30-365 days, 54%; and > 365 days, 83%). Patients on the regional waiting list had an 18% mortality rate while awaiting transplantation. These results were incorporated into a mathematical model describing survival as a function of reTx rate, assuming a limited supply of donor livers. ReTx improves the 1-year survival rate for patients undergoing PTx but decreases overall survival (survival of all candidates) for liver transplantation. In the current era of persistently insufficient donor numbers, strategies based on minimizing the use of reTx, especially in the case of patients in whom chances of success are minimal, will result in the best overall rate of patient survival.

Adolescent↗
PubMed1992

Trimethoprim-sulfamethoxazole compared with ciprofloxacin for the prevention of urinary tract infection in renal transplant recipients. A double-blind, randomized controlled trial.

BACKGROUND: Prophylaxis with low-dose trimethoprim-sulfamethoxazole has been shown to be cost-effective in the prevention of urinary tract infections, pyelonephritis, urosepsis, and pneumocystis pneumonia in renal transplant recipients. Ciprofloxacin, effective against almost all urinary tract pathogens in this patient population, represents a promising alternative prophylactic agent for patients unable to tolerate trimethoprim-sulfamethoxazole due to toxicity. METHODS: We conducted a randomized, double-blind trial to compare low-dose trimethoprim-sulfamethoxazole with ciprofloxacin for the prevention of urinary tract infections in renal transplant recipients. Patients received either ciprofloxacin (250 mg) or trimethoprim-sulfamethoxazole (80 mg trimethoprim, 400 mg sulfamethoxazole) daily for 6 months following transplantation. Treatment was considered successful if patients completed the 6-month course and 3-month follow-up period without evidence of urinary tract infection or drug-related toxicities. RESULTS: Of 103 eligible patients, 51 received ciprofloxacin and 52 received trimethoprim-sulfamethoxazole. At 6 months, treatment was successful in 75% (38 of 51) receiving ciprofloxacin and 71% (37 of 52) treated with trimethoprim-sulfamethoxazole (P = 0.87, relative risk 1.04, 95% confidence limits 0.83 to 1.33). Thirteen patients (25%) receiving trimethoprim-sulfamethoxazole withdrew from the study-4 for resistant urinary tract infection and 9 for drug-related toxicity, while 3 (6%) of the patients receiving ciprofloxacin withdrew because of drug-related toxicity (P = 0.016, relative risk of urinary tract infection or adverse event 0.24, 95% confidence limits 0.07 to 0.78). At 9 months, all 38 patients who completed the 6-month course of ciprofloxacin remained free of urinary tract infection, while an additional 4 patients who had received trimethoprim-sulfamethoxazole prophylaxis (total of 8 patients over the 9 months) developed urinary tract infections (P = 0.006, Fisher's exact test for urinary tract infection alone). Pneumocystis pneumonia occurred in a total of 7 (14%) patients who were randomized to ciprofloxacin, but 2 of the 7 had withdrawn from the study at least 2 weeks prior to the diagnosis of pneumocystis pneumonia. There were no cases of pneumocystis pneumonia in patients receiving trimethoprim-sulfamethoxazole (P = 0.006). Following completion of the study, monthly aerosolized pentamidine administered in conjunction with ciprofloxacin has provided complete protection against urinary tract infection and pneumocystis pneumonia in 30 transplant recipients unable to tolerate trimethoprim-sulfamethoxazole therapy. CONCLUSIONS: Ciprofloxacin is at least as effective as trimethoprim-sulfamethoxazole in the prevention of urinary tract infection in renal transplant recipients, and is better tolerated. Ciprofloxacin prophylaxis is associated with a higher incidence of pneumocystis pneumonia than is trimethoprim-sulfamethoxazole therapy. An uncontrolled follow-up study suggests that ciprofloxacin prophylaxis combined with monthly aerosolized pentamidine may be efficacious in preventing both urinary tract infection and pneumocystis pneumonia in renal transplant recipients.

Adult↗
PubMed1992

Symptomatic cytomegalovirus disease in the cytomegalovirus antibody seropositive renal transplant recipient treated with OKT3.

A prospective study to investigate risk factors for CMV disease was conducted in 94 renal transplant recipients. CMV disease was defined as either unexplained fever for greater than 3 days with viremia or unexplained fever for greater than 3 days with isolation of CMV from the urine or throat wash and at least one of the following: leukopenia, elevated serum alanine aminotransferase, or biopsy-proved invasive tissue infection of the lung or gastrointestinal tract. Fifty-three patients received immunosuppressive regimens consisting of prednisone and cyclosporine, with or without azathioprine. The remaining 41 patients were treated with these agents plus OKT3 (21 received OKT3 to treat rejection, 20 received OKT3 prophylactically). Thirty-seven patients were at minimal risk of CMV disease (donor and recipient seronegative for CMV); 12 patients were at risk of primary disease (donor seropositive, recipient seronegative), and 45 were at risk of reactivation disease (recipient seropositive at the time of transplantation). The incidences of CMV disease in the 3 groups were 0%, 58%, and 36%, respectively. Although the incidence of CMV disease in patients at risk of primary disease was not influenced by the immunosuppressive regimen, immunosuppression had a profound effect on the occurrence of CMV disease in CMV-seropositive transplant recipients. The incidence of CMV disease in those receiving OKT3 was 59%; but only 21% in those who did not receive OKT3. OKT3 increased the risk of CMV disease five-fold (odds ratio 5.2 (95% confidence limits 1.4-17.5)). In the CMV-seropositive patient, OKT3 was also the most important predictor of CMV disease by multivariate analysis (P less than 0.002). A pilot study of preemptive therapy with ganciclovir (2.5 mg/kg daily during OKT3 therapy) in 17 patients decreased the incidence of CMV disease without appreciable toxicity.

Adult↗
PubMed1992

Liver transplantation for primary hepatic cancer.

Although early survival following transplantation for primary hepatic cancer is excellent, previously reported high recurrence rates have generally discouraged liver replacement for this indication. Since the inception of the Boston Center for Liver Transplantation (BCLT) in 1983, 33 of 383 (8.6%) liver allograft recipients have undergone orthotopic transplantation as definitive treatment for otherwise unresectable cancer. Diagnoses included hepatocellular carcinoma (HCCA) in 24 patients (73%), and cholangiocarcinoma (CHCA) in 9 patients (27%). Actuarial survival rates for patients with hepatocellular carcinoma were 71%, 56%, and 42% at 1, 2, and 3 years, respectively. The actuarial survival rates for patients with cholangiocarcinoma were 89% at 6 months, and 56% at 1, 2, and 3 years. Of the nine patients with cholangiocarcinoma, 56% (5/9) developed recurrent disease. Although this recurrence rate is disheartening, because of the lack of other morbidity, long-term survival in these patients is comparable to patients with HCCA. In contrast, recurrent hepatocellular carcinoma developed in 25% of recipients (5/20) who survived longer than 3 months posttransplantation. Other causes of death in patients with hepatocellular carcinoma included perioperative complications, 16.6% (4/24); sepsis, 8.3% (2/24); coronary artery disease, 4.2% (1/24); and lymphoma, 4.2% (1/24). Favorable prognostic factors included: primary tumor less than 3 cm in size and absence of associated cirrhosis. These results emphasize that orthotopic liver transplantation can provide a long-term cure for approximately 50% of patients whose primary hepatic malignancy is unresectable by conventional procedures.

Adenoma, Bile Duct↗
PubMed1992

The effects of OKT4A monoclonal antibody on cellular immunity of nonhuman primate renal allograft recipients.

Significant differences in cellular responses were found among allograft recipients treated with various OKT4A mAb protocols. Recipients of multiple infusion low-dose and 2-bolus OKT4A immunosuppressive regimens regularly showed potent donor-specific cytotoxic CD8+ and CD4+ intragraft T cells and donor-reactive PBMC in MLC tests. In contrast, PBMC isolated from recipients of high-dose OKT4A therapy generally showed very weak or no response to donor-antigens during the later posttransplant periods. Furthermore, an absence of IL2-responsive intragraft cells was found to correlate with stable graft function in these recipients. We conclude that OKT4A mAb, in high doses, can block allosensitization and induce donor-specific nonresponsiveness in vivo. An OKT4A-based therapy, therefore, may have the potential of inducing long-lasting donor-specific immunosuppression, or even tolerance.

Animals↗
PubMed1991

Prognosis after initial recurrence of cutaneous melanoma.

We reviewed 231 patients who developed recurrent disease 1 to 218 months after surgical therapy for clinical stage I cutaneous melanoma. Metastatic lesions amenable to surgery, including visceral recurrences, were resected. Adjuvant systemic chemotherapy/immunotherapy or regional hyperthermic perfusion was added in patients with unresected disease. Local irradiation was employed for nonresectable brain or other isolated symptomatic metastases. The overall 5-year survival rate after initial recurrence was 36%. In patients with soft tissue or nodal recurrence, the 5-year survival rates were 49% and 38%, respectively; six (11%) of 53 patients whose initial recurrence was in a visceral organ achieved prolonged remission. Primary lesion anatomic site, thickness, pathologic type, and interval from initial therapy to recurrence were unrelated to survival. Significant prognostic factors included the site of initial metastasis, stage of primary disease, and the successful complete eradication of gross disease by surgical excision or intensive chemotherapy.

Adult↗
PubMed1991

Long-term metabolic and quality of life results with pancreatic/renal transplantation in insulin-dependent diabetes mellitus.

Evaluation of whole-organ pancreas transplantation in the therapy of IDDM has been difficult because of generally poor graft survival and significant complications in past experience. We report a technically successful simultaneous pancreas/kidney transplant program with patient and graft survival of 85% over 3 years of follow-up (mean 21 months) in 33 subjects with IDDM. Glucose metabolism was normalized without need for exogenous insulin immediately posttransplant in all but one recipient and remained normal in 85% of recipients. The outcome in pancreas/kidney recipients was compared with that in 18 insulin-dependent diabetic recipients of kidney transplant only performed in the same period. Quality of life was assessed with one general and one diabetes-specific questionnaire. General quality of life issues improved significantly in both pancreas/kidney and kidney recipients, but diabetes specific quality of life improved only in the pancreas/kidney recipients. Pancreas/kidney recipients required twice as long a period of hospitalization for the transplant and two times as many readmissions for a variety of complications. Only a minority of hospital admissions was strictly attributable to the pancreas graft. Of the five deaths in the pancreas/kidney recipients, two were attributable to the pancreas transplant. Pancreas transplantation in IDDM can now be accomplished with a high degree of success, resulting in normalized glucose metabolism and with overall mortality similar to kidney transplantation alone. Successful pancreas transplantation improves quality of life with respect to diabetes but this benefit is accomplished at a cost of increased hospital admissions and complications related to the transplanted pancreas. The effects of pancreas transplantation on the long-term complications of insulin-dependent diabetes remain unknown.

Adult↗