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Biomedical subjects

F L Delmonico

Publications and source records attributed to F L Delmonico.

At least 55 records · Page 3Linked to original sources
PubMed1996

Anti-CD4 monoclonal antibody therapy.

Because they can be selected to target only cells which are crucial for rejection, monoclonal antibodies (mAbs) offer enormous potential for specific manipulation of the immune response. Interest in the clinical potential of anti-CD4 mAbs has been heightened by the demonstration, in experimental models, that such therapy can produce long-term donor-specific non-responsiveness. Early clinical trials using two murine anti-CD4 mAbs (BL4 and mT-151) were discouraging, with over 50% of recipients suffering early rejection episodes. Another murine preparation, OKT4A, was initially found to prolong allograft survival in non-human primates. Limited clinical trials revealed that this mAb was well tolerated, that most recipients produced an antimurine response, and that only 26% of patients suffered rejection episodes during the first 3 post-operative months. Another murine preparation, Max. 16H5, has been reported to reverse late onset acute rejection episodes as effectively as, but more safely than, conventional immunosuppression. More recent interest has focused upon humanized recombinants of these earlier murine anti-CD4 preparations. cMT-412, has been studied in recipients of heart or heart-lung allografts. These patients were observed to have less frequent and markedly delayed rejection episodes, fewer infectious complications, and better overall survival than that observed in an ATG-treated control group. Further studies are thus being undertaken. A CDR grafted IgG4 preparation of OKT4A has also been studied. This molecule (OKTcdr4a) contains only 8% of the parent murine sequence while retaining the binding affinity of OKT4A for the human CD4 antigen. In a pilot trial, biopsy-proven reversible rejection episodes were observed in 2/11 (18%) of renal allograft recipients. There were no allograft failures and no antibody response to the mAb. These and other trials emphasize the intense interest in immunosuppressive regimens incorporating anti-CD4 mAbs as well as the difficulties encountered in defining optimal protocols. Nevertheless, the impressive results observed in rodent and non-human primate models suggest that these agents are likely to play an important role in future immunosuppressive protocols, particularly those designed to induce tolerance.

Animals↗
PubMed1994

CDR-grafted OKT4A monoclonal antibody in cynomolgus renal allograft recipients.

In an attempt to improve therapeutic efficacy and limit antimurine responses to the IgG2a monoclonal antibody OKT4A, humanized complementarity determining region (CDR)-grafted OKT4A mAbs (IgG1 and IgG4 isotypes) were developed from the murine molecule. Preclinical evaluation was undertaken in 12 cynomolgus renal allograft recipients (IgG1, n = 7; IgG4, n = 5). Control animals received either no therapy (n = 2) or OKT3 (n = 2). The mAbs were given as a single 10-mg/kg bolus on the day of transplantation or as multiple 1-mg/kg doses. Mean allograft survival (+/- SEM) was 9 +/- 0.7 days in control animals; 45.2 +/- 6.0 days, P = 0.002 (single dose, n = 5), and 39 +/- 5.0 days, P = 0.053, (multiple doses, n = 2) in IgG1-treated animals; and 35.3 +/- 7.2 days, P = 0.034, (single dose, n = 3) and 15.5 +/- 6.5 days, P = .251 (multiple doses, n = 2) in IgG4-treated animals. Whereas IgG4-treated animals showed coating of peripheral blood CD4+ T cells, significant CD4+ T cell depletion was observed in IgG1-treated animals. These results confirm the retained immunosuppressive efficacy of humanized OKT4A antibodies. In contrast to murine mAbs, the use of these agents would not preclude sequential treatment with mAbs directed against different epitopes. The fact that rejection can occur despite peripheral blood CD4+ cell depletion suggests that indefinite control of allograft rejection in primates may require more intensive therapy than has proved effective in rodent models.

Animals↗
PubMed1994

Second renal transplantations. Ethical issues clarified by outcome; outcome enhanced by a reliable crossmatch.

OBJECTIVE: To determine whether the appropriate use of scarce donor resources has been accomplished by renal retransplantation by reviewing the initial and long-term outcomes of second-renal transplant recipients at the Massachusetts General Hospital, Boston. PATIENTS AND RESULTS: With a mean follow-up of nearly 5 years following transplantation, 54 (68%) of 80 second-transplant recipients had functioning allografts (allograft failure was defined by patient death or a return to dialysis). Rejection was the most common cause of failure (14 [54%] of 26 patients). The 1-, 3-, and 5-year actuarial allograft survival rates were 86%, 78%, and 69%, respectively, which were not significantly different from the survival rates of primary allografts at this center. These results support the continued approach of providing both cadaver-donor and living-donor renal allografts for recipients whose primary renal allograft has failed. The antiglobulin crossmatch may have contributed to the successful outcome by accurately determining compatibility and by averting early rejection failures. CONCLUSIONS: Health care policy reviewers should clearly distinguish the prospects for successful second renal transplants from the outcomes of extrarenal retransplantation. Moreover, because excellent second-renal allograft survival is attainable and comparable to primary-renal allograft survival and because the costs are comparable, restricting suitable patients to subsequent lifelong dialysis becomes unethical.

Adult↗
PubMed1994

Management of the renal allograft recipient: immunosuppressive protocols for long-term success.

To determine the benefits of long-term cyclosporine (CsA) immunosuppression, renal allograft recipients were randomly assigned to a protocol of either: CsA+azathioprine (Aza)+prednisone (TD), or to a protocol in which CsA was discontinued from the regimen of Aza+prednisone (CsA D/C). With a mean follow-up of nearly 7 years since transplantation, 30/47 (64%) CsA D/C and 27/45 (60%) TD had functioning allografts. Although long-term survivals were similar, hazards of the CsA D/C protocol were evident (40% rate of acute rejection following CsA D/C). Conversely, continued CsA in the TD protocol provided the opportunity for prednisone reduction, or even complete prednisone withdrawal in selected patients. A TD protocol which can provide equivalent long-term success, and eventually lower or omit prednisone, is preferable to a protocol of CsA D/C.

Acute Disease↗
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↗
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

The high-risk liver allograft recipient. Should allocation policy consider outcome?

The Boston Center for Liver Transplantation has accumulated one of the larger series of liver allograft recipients. This review has provided an opportunity to examine recent pronouncements by Medicare regarding patient selection and survival and to question whether the current allocation scheme best utilizes a scarce supply of donor liver allografts. Patients with primary biliary cirrhosis, sclerosing cholangitis, and metabolic derangements have enjoyed excellent survival: in aggregate, 78.9% at 1 year. In contrast, patients suffering from acute hepatic failure, patients requiring life support, or patients with primary graft failure who need a second liver transplant did poorly compared with other recipient groups: 45% 1-year survival. This center's experience reflects a more realistic expectation of patient survival because it considers the high-risk recipient by diagnosis and urgency status. This study also suggests that assessment of outcome should be a component of allocation planning in the future.

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↗
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↗
PubMed1990

In vivo effects of monoclonal antibody to ICAM-1 (CD54) in nonhuman primates with renal allografts.

These studies test whether allograft rejection can be blocked by interference with leukocyte adhesion, using a murine IgG2a mAb (R6.5) reactive with monkey ICAM-1 (CD54). In 16 Cynomolgus renal allograft recipients, R6.5 was administered prophylactically as the sole immunosuppressive agent for 12 days (0.01 to 2 mg/kg/day). Survival in 14 recipients with technically successful grafts was significantly prolonged (24.2 +/- 2.4 vs 9.2 +/- 0.6 days for controls; p less than 0.001). Intercellular adhesion molecule-1 (CD54) (ICAM-1) was expressed on vascular endothelium in the kidney and other organs in the monkey in a pattern similar to that in humans. During cellular rejection in controls, ICAM-1 expression increased on endothelial cells, infiltrating mononuclear leukocytes and tubular cells. Biopsies during R6.5 administration showed decreased T cell infiltration (CD2, CD8, CD4) compared with controls and decreased arterial endothelial inflammation. No changes occurred in circulating T cells, aside from variable coating with mIgG. In six of eight other recipients R6.5 administration (0.5 to 2 mg/kg/day for 10 days) reversed preexisting rejection that resulted from taper of Cyclosporine to subtherapeutic levels. Responding grafts showed decreased edema and hemorrhage but no consistent change in the infiltrate. At 1 h after the first dose, mouse IgG deposited primarily on the graft vascular endothelium without any change in the inflammatory infiltrate. Mouse IgG also deposited on the endothelium of normal organs without eliciting an inflammatory response and was cleared from the endothelium within 4 days. Inasmuch as the principal site of binding was the vascular endothelium, we hypothesize that the antibody blocks adhesion to graft ICAM-1 molecules on the vessels. Anti-ICAM-1 also binds to recipient cells and may interfere with Ag presentation and/or T cell interactions. Whatever the mechanism(s), these studies indicate that an anti-ICAM-1 antibody inhibits T cell mediated injury in vivo, and that ICAM-1 is a critical molecule in the pathogenesis of allograft rejection.

Animals↗
PubMed1990

A randomized clinical trial of prophylactic OKT3 monoclonal antibody in liver allograft recipients.

Seventy-nine hepatic allograft recipients were randomized to receive either conventional immunosuppression, including cyclosporine, azathioprine, and steroids (41 patients), or investigational therapy in which OKT3 replaced cyclosporine during the first postoperative week (38 patients). Early rejection occurred in 29 patients (71%) in the conventional group and 15 patients (39%) in the OKT3 group. Posttransplantation renal dysfunction occurred in 12 patients (29%) in the conventional group and 6 patients (16%) in the OKT3 group. Mean initial hospital stay was 34.1 +/- 18.8 days in the conventional group compared with 29.1 +/- 16.8 days in the OKT3 group. Cumulative patient survival (mean follow-up, 17.8 +/- 7.1 months) was 73.2% (30/41) for the conventional group and 84.2% (32/38) for the OKT3 group. Prophylactic OKT3 is indicated especially for liver allograft recipients with other complicating conditions that make management of early rejection unusually difficult.

Adult↗
PubMed1990

Long-term, low-dose cyclosporine treatment of renal allograft recipients. A randomized trial.

Ninety-two adult renal allograft recipients, receiving baseline immunosuppression with CsA and prednisone, were assigned randomly to one of the following regimens. CsA was discontinued (D/C group) in 47 recipients who were then maintained on Aza and prednisone; or Aza was added to continued low-dose CsA and prednisone (triple drug [TD] group) in 45 patients. Entry into the study required an absence of rejection and a stable creatinine for at least four months prior to randomization. The mean month of randomization was 8.34 +/- 2.9 for the D/C group, and 7.2 +/- 3.2 for the TD group. Following randomization, a significantly greater rate of rejection (P less than .01) was observed in the D/C group (40%) than in the TD group (13%). With a mean follow-up of 30 months, 41/47 of D/C allografts (87.2%) and 39/45 TD allografts (86.6%) were functioning. Nevertheless, rejection had a persistent adverse effect on allograft function, in both the D/C and TD groups, up to 36 months following randomization. Parameters such as donor-type and rejection prior to randomization did not identify recipients at risk for rejection following randomization. Therefore, although the CsA withdrawal regimen might be ideal, the opportunity to select appropriate candidates remained elusive. In contrast, the safety of the TD regimen became apparent. Neither significant nephrotoxicity nor hypertension was observed, and the opportunity for less daily prednisone was evident. Despite its additional cost, the TD regimen utilizing indefinite low-dose CsA, is preferred.

Adult↗