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Biomedical subjects

A B Cosimi

Publications and source records attributed to A B Cosimi.

At least 91 records · Page 5Linked 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↗
PubMed1995

Mixed allogeneic chimerism and renal allograft tolerance in cynomolgus monkeys.

We have developed a nonmyeloablative preparative regimen that can produce mixed chimerism and renal allograft tolerance between MHC-disparate nonhuman primates. The basic regimen includes ATG, nonmyeloablative total-body irradiation (TBI, 300 rads), thymic irradiation (TI, 700 rads), and donor bone marrow infusion. Kidney allografts from MHC-mismatched donors were transplanted with various manipulations of the preparative regimen. Monkeys treated with the basic regimen alone (n = 2) rejected allografts by day 15. With the addition of cyclosporine (CsA) for one month (n = 3), one monkey developed multilineage mixed chimerism and renal allograft tolerance thereafter (> 430 days). To reduce the toxicity of the preparative regimen, TBI was fractionated to 150 rads on two successive days in subsequent studies. All monkeys receiving this modified regimen (n = 4) developed multilineage chimerism with fewer side effects and accepted renal allografts long-term with no further immunosuppression (196 days, 198 days, > 150 days, and > 40 days). In long-term survivors, donor-specific nonreactivity was confirmed by MLR and skin transplantation. Three monkeys treated with the basic regimen plus CsA but with only 150 rads of TBI (n = 1) or no TBI (n = 2) did not develop multilineage chimerism and grafts were rejected (day 40-50) soon after the CsA discontinuation. Monkeys treated with the same regimen, but without DBM (n = 2), rejected kidney allografts by day 52. Therefore, at least transient engraftment of DBM appears to be essential for induction of donor specific tolerance in this monkey model.

Animals↗
PubMed1995

Inhibition of the effects of TNF in renal allograft recipients using recombinant human dimeric tumor necrosis factor receptors.

Tumor necrosis factor alpha (TNFa) and lymphotoxin (LT) or TNF beta are closely linked cytokines produced by macrophages and activated T lymphocytes, which play important regulatory roles in the immune response to allografts. They have also been implicated as mediators of the adverse reactions observed during OKT3 therapy. Therefore, anti-TNF agents could be useful both for immunosuppression and for limiting the systemic response observed in patients receiving OKT3. Recombinant TNFR:Fc is a fusion protein that binds TNFa and LT, thereby neutralizing their effects in vitro. The present study investigates the potential clinical application of TNFR:Fc in a nonhuman primate renal allograft model. Cynomolgus renal allograft recipients were treated with TNFR:Fc induction therapy alone or in combination with subtherapeutic doses of cyclosporine. Control animals received no immunosuppression or subtherapeutic cyclosporine. TNFR:Fc, administered as the only immunosuppressive agent, successfully prolonged renal allograft survival in the majority of treated animals. The prolongation of allograft survival was even more impressive when TNFR:Fc was combined with subtherapeutic doses of cyclosporine. Onset of rejection was significantly delayed as well in the TNFR:Fc treated groups. No adverse side effects were observed in any of the TNFR:Fc treated animals. Precursor cytotoxic T cells were detected in peripheral blood samples of treated recipients but the level of effector CTLs in vivo was below the threshold of detection. These results demonstrate that TNFR:Fc can be safely administered and is effective in prolonging renal allograft survival and in delaying the onset of rejection when administered alone or in combination with cyclosporine.

Animals↗
PubMed1995

Future of monoclonal antibodies in solid organ transplantation.

The ultimate objective of immunosuppressive therapy is to block transplant recipient reactivity to allograft incompatibilities while sparing other responses. Increased clarification of rejection mechanisms has made possible the precise suppression of specific elements of the immune response using murine anti-human monoclonal antibodies. In addition, recombinant DNA technology has made available novel agents including "humanized," bispecific, or toxin-conjugated molecules, which avoid some of the limitations of murine reagents. Using such agents, donor-specific tolerance has been induced in experimental models after a limited course of therapy directed against selected effector cell surface-associated molecules such as CD4, CD25, and CD54. It remains to be determined how such observations can be successfully transferred to the human situation. It seems likely, however, that as new molecular agents are developed, increasingly effective suppression of specific cellular targets will become an essential element of clinical protocols. Such agents may provide long-term immunosuppression with limited periods of immunosuppressive agent administration.

Animals↗
PubMed1995

Real-time monitoring of renal function during ischemic injury in the rhesus monkey.

The presence of delayed graft function (DGF) following cadaver donor renal transplantation is associated with inferior graft survival as well as decreased patient survival. Delay in onset of function eliminates a valuable indicator of allograft viability, which is not easily replaced by standard diagnostic procedures. The purpose of this study was to demonstrate that a new clearance technique could be used to measure renal function minute to minute and under conditions similar to those observed in humans in the immediate posttransplantation period. A monkey model was used to provide controlled conditions. Increasing levels of ischemic injury were produced in 12 Rhesus monkeys by renal hilum cross-clamping. Real-time measurements of glomerular filtration rate (GFR) were obtained from the rate of clearance of the extracellular fluid of the GFR agent 99mTc-DTPA, as measured with a specially designed external radioactivity counting device called the ambulatory renal monitor, or ARM. GRF was measured every 2-5 min as the slope (k) of the log of activity measured minute to minute versus time. GFR measurements were correlated with blood urea nitrogen (BUN), plasma creatinine (Cr), routine light microscopy, and measurement of proliferating cell nuclear antigen (PCNA), a marker of cell proliferation. Large changes in renal function due to ischemia or ureteral obstruction were observed within minutes. In addition, the rate constant on Day 1 was predictive of peak serum Cr(R =--0.86, R2=.74, p = .0001). Acute tubular necrosis (ATN) resolution was reflected more quickly when using the rate constant (Day 1) than when using either BUN or plasma Cr (Day 3-4). Because of renal functional reserve, BUN and plasma Cr were relatively insensitive indicators of mild to moderate reductions in GFR as compared with the rate constant. We conclude that ARM is a simple method which provide an accurate, near real-time GFR readout with potential applications not only for the clinical management of patients with DGF, but also as a research tool in acute renal failure (ARF).

Animals↗
PubMed1995

Cardiovascular complications following liver transplantation.

BACKGROUND: As the indications for liver transplantation broaden to include older and more critically ill patients, the likelihood of encountering unsuspected cardiovascular disease increases. PURPOSE: This study examined the frequency, type, and subsequent outcome of intra- and postoperative cardiovascular complications that occurred during the first 6 months following liver transplantation. METHODS: The records of 146 consecutive patients who underwent primary liver transplantation were reviewed retrospectively to determine the occurrence of major (myocardial infarction or reversible ischemia, pulmonary edema, cardiogenic shock, symptomatic rhythm disturbances, or pulmonary embolism) and minor (transient hypertension, hypotension, atrial or ventricular premature beats) cardiac events. The relation between such events and actuarial patient survival was evaluated. Stepwise logistic regression analysis was also employed to identify those pre-operative variables that predicted an increased risk of postoperative events or mortality. RESULTS: Cardiac events directly caused or contributed to 4 deaths (2.7%). Ventricular tachycardia/fibrillation was the most frequent intra-operative cardiac complication (3.4%); transient hypotension (post-reperfusion syndrome) was the most common minor event (20%). Thirty-four recipients (23%) developed a major postoperative cardiac complication including pulmonary edema (9%), myocardial ischemia or infarction (5.4%), new dilated cardiomyopathy (3.4%), and ventricular tachycardia (2.7%). Pre-existing cardiac disease and older age (mean age 49 +/- 8 years) at transplantation were the only independent predictors of a major complication. Major cardiac events did not affect 6 month survival but were associated with a lower 5-year survival rate (event: 32% vs event-free: 52%; p = 0.04). The frequency of major intraoperative (21% vs 2%; p = 0.0005) and postoperative (57% vs 17%; p = 0.0001) cardiac complications was significantly higher for recipients with known heart disease (Group A) compared with those without pre-existing heart disease (Group B). Five-year survival in Group A patients was 36% versus 50% for Group B patients; p = 0.45. CONCLUSION: One or more cardiovascular complications occurred in over 70% of liver transplant recipients. Major events were associated with a lower likelihood of long-term survival. Older patients, particularly those with pre-existing but compensated heart disease, are at greatest risk for a major cardiac event and may require more extensive pre-operative risk assessment.

Adolescent↗
PubMed1994

Should liver transplantation be performed for patients with hepatitis B?

Because of the almost universal recurrence of hepatitis B surface antigenemia (HBsAg) after liver transplantation, some centers have questioned whether these patients are appropriate allograft candidates. Since January 1984, 51 patients with hepatitis B (HBV) underwent OLT at our center. No therapy was given to prevent reinfection. Three patients underwent retransplantation. The indications for transplant included fulminant HBV (13 patients), chronic HBV (33 patients), and hepatocellular carcinoma (HCCA) in addition to HBV (5 patients). Incidental HCCA was found in 2 of the 33 patients thought to have only chronic HBV. Actuarial survival for the entire group was 57% at 1 year and 54% at 3 years. Of the 23 patients who died, only 4 deaths were attributable to recurrent HBV liver disease. Four patients survived less than 4 days due to primary graft nonfunction. Ten patients died in the first 3 months from sepsis. Although all patients who died beyond 30 days had recurrent HBsAg, only 4 deaths were attributable to recurrent HBV. The remaining 5 deaths were caused by portal vein thrombosis, bile leak, lymphoma, pancreatitis, and sepsis occurring at 15 months. Excluding the 4 patients who died from primary graft nonfunction, actuarial survival was 63% at 1 year and 60% at 3 years. Of the 28 survivors, 24 are HBsAg positive; however, only 5 have recurrent HBV liver disease. Multiple factors were evaluated to determine their influence on survival; i.e., HBV serology, United Network for Organ Sharing status, fulminant versus chronic HBV, incidence of rejection, immunosuppression, transfusion requirements, and presence of HCCA. Of these, only the presence of HCCA adversely affected outcome. Of the 7 patients with HCCA and HBV, 6 patients died within the first 6 months and 1 patient has recurrent HBV liver disease at 25 months. Actuarial survival excluding those patients with HCCA was 64% at 1 year and 61% at 3 years. Based on our results, patients with HBV and associated HCCA have a poorer prognosis and should probably be excluded from transplantation. Although the survival for patients with HBV undergoing liver transplantation is inferior to that expected in patients with some other diagnoses, long-term survival can be achieved in a majority of these patients despite recurrence of HBsAg. We believe that appropriately selected patients with a diagnosis of HBV alone should continue to be candidates for liver allografts.

Adolescent↗
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↗