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Biomedical subjects

C Anasetti

Publications and source records attributed to C Anasetti.

At least 163 records · Page 9Linked to original sources
PubMed1992

Coexpression and functional cooperation of CTLA-4 and CD28 on activated T lymphocytes.

T cell costimulation by molecules on the antigen presenting cell (APC) is required for optimal T cell proliferation. The B7 molecule on APC binds the T lymphocyte receptor CD28, triggering increased interleukin 2 (IL-2) production and subsequent T cell proliferation. CTLA-4 is a predicted T cell membrane receptor homologous to CD28, which also binds the B7 counter receptor, but whose distribution and function are unknown. Here we have developed monoclonal antibodies (mAbs) specific for CTLA-4 and have investigated these questions. mAbs were produced that bound CTLA-4 but not CD28, and that blocked binding of CTLA-4 to B7. CTLA-4 expression as measured by these mAbs was virtually undetectable on resting T cells, but was increased several hundred-fold during T cell activation. On activated lymphocytes, CTLA-4 was expressed equally on CD4+ and CD8+ T cell subsets and was coexpressed with CD25, CD28, and CD45RO. CTLA-4 expression was lower than that of CD28, reaching a maximum of approximately 1/30-50 the level of CD28. Despite its lower expression, CTLA-4 was responsible for much of the B7 binding by large activated T cells. Anti-CTLA-4 mAb 11D4 and anti-CD28 mAb 9.3 acted cooperatively to inhibit T cell adhesion to B7, and to block T cell proliferation in primary mixed lymphocyte culture. When coimmobilized with anti T cell receptor (TCR) mAb, anti-CTLA-4 mAbs were less effective than anti-CD28 mAb 9.3 at costimulating proliferation of resting or activated T cells. However, coimmobilized combinations of anti-CD28 and anti-CTLA-4 were synergistic in their ability to augment anti-TCR-induced proliferation of preactivated CD4+ T cells. These results indicate that CTLA-4 is coexpressed with CD28 on activated T lymphocytes and cooperatively regulates T cell adhesion and activation by B7.

Abatacept↗
PubMed1992

Acute graft-versus-host disease: analysis of risk factors after allogeneic marrow transplantation and prophylaxis with cyclosporine and methotrexate.

Previous studies of risk factors for acute graft-versus-host disease (GVHD) involved patients receiving predominantly single-agent prophylaxis. Therefore, a retrospective analysis was performed on 446 patients, from a single institution, who received transplants of marrow from HLA-identical siblings and the combination of cyclosporine (CSP) and methotrexate (MTX) to determine risk factors for acute GVHD associated with this more effective form of GVHD prophylaxis. The incidences of Grades II-IV and Grades III-IV (severe) acute GVHD were 35% and 16%, respectively. Increased clinical grades of acute GVHD in patients without advanced malignant disease were associated with a decreased survival. In a multivariate Cox regression analysis, risk factors associated with the onset of Grades II-IV acute GVHD were sex mismatch and donor parity (P = .001), increased dose of total body irradiation (TBI) (P = .001), and reduction to less than 80% of the scheduled dose of MTX (P = .02) or CSP (P = .02). The multivariate analysis indicated a relative risk of 1.37 for acute GVHD in a group defined as having advanced malignant disease at transplant; however, this difference failed to reach conventional levels of statistical significance (P = .07). Reduction of MTX and CSP occurred in up to 36% and 44% of patients, respectively, primarily because of renal or hepatic dysfunction. The periods of increased risk for the onset of acute GVHD were up to 1 week after a reduction of MTX and 2 weeks after a reduction in CSP. When only patients who developed Grades II-IV acute GVHD were considered, the more severe acute GVHD of Grades III-IV was associated with increased patient age of 40 years or greater (P = .05) and dose reductions of CSP (P = .008). Serologic status of patient and donor for cytomegalovirus (CMV), HLA antigens in the A and B loci, and isolation in a laminar air flow room during marrow transplantation, all previously identified as risk factors for acute GVHD, were not confirmed as risk factors in this study population. The toxicity of MTX and CSP and the development of acute GVHD from inadequate immunosuppression because of dose reduction warrants further trials with potentially less toxic immunosuppressive agents. Risk factors for acute GVHD should be considered in clinical management and in the design of clinical trials.

Adult↗
PubMed1992

Immunosuppressive therapy of aplastic anemia: results of a prospective, randomized trial of antithymocyte globulin (ATG), methylprednisolone, and oxymetholone to ATG, very high-dose methylprednisolone, and oxymetholone.

Sixty-eight patients with moderate (n = 15) or severe (n = 53) aplastic anemia were entered into a prospective, randomized, two-arm treatment study comparing antihuman thymocyte globulin (ATG), lower-dose methylprednisolone (LDM) and oxymetholone to ATG, higher-dose methylprednisolone (HDM), and oxymetholone. There were no differences between the two groups when comparing age, sex, etiology of aplasia, disease duration, severity of aplasia, or pretherapy granulocyte counts. Side effects of LDM and HDM were similar. Of the 64 patients evaluable for response to therapy, 12 of 33 (36%) who received LDM had complete, partial, or minimal responses compared with 15 of 31 patients (48%) who received HDM (P = .33). Actuarial survival at 4 years is 43% for patients in the LDM group and 47% for patients in the HDM group (P = .99). Causes of death included hemorrhage, infection, evolution to acute leukemia, and complications of subsequent bone marrow transplantation. Long-term complications included paroxysmal nocturnal hemoglobinuria (n = 3), evolution to myelodysplasia or acute leukemia (n = 6), and recurrent aplasia (n = 6). We were unable to show a significant difference in toxicity, response rate, or survival for patients treated with ATG, oxymetholone, and LDM compared with patients who received ATG, oxymetholone, and HDM.

Adult↗
PubMed1992

Phase II trial of recombinant human granulocyte-macrophage colony-stimulating factor in patients undergoing allogeneic bone marrow transplantation from unrelated donors.

The safety and possible efficacy of recombinant human granulocyte-macrophage colony-stimulating factor (rhGM-CSF) were evaluated in 40 consecutive patients who received transplants from unrelated donors. rhGM-CSF was administered by 2-hour daily intravenous infusion from day 0 to day 20 or day 27 after the marrow infusion. These patients were compared with 78 historical patients who received transplants from unrelated donors who did not receive rhGM-CSF. The rhGM-CSF-treated patients were older (P = .037) and were treated less frequently in laminar air flow rooms (P = .005) than were control patients. However, the rhGM-CSF-treated group had a higher proportion of "good risk" patients with chronic myelogenous leukemia in chronic phase (P = .006) than did the comparison group (P = .017), rendering comparisons of transplant-related complications not meaningful. rhGM-CSF was well tolerated and did not adversely increase the incidence of graft rejection or increase the incidence and severity of acute graft-versus-host disease. The median day the absolute neutrophil count reached 500/mm3 in patients who received rhGM-CSF was day 21, which was not different from that of historical patients. Nevertheless, the numbers of febrile days and septicemic episodes within the first 28 days in patients who received rhGM-CSF were less than in historical patients. The probability of nonrelapse mortality at 1 year in patients who received rhGM-CSF was 22%. In view of the retrospective nature of the control group, we cannot conclusively determine whether rhGM-CSF administration was beneficial. A prospective, randomized controlled study of rhGM-CSF is required to confirm these suggestive data.

Adult↗
PubMed1992

Treatment of acute graft-versus-host disease with a nonmitogenic anti-CD3 monoclonal antibody.

Treatment with the monoclonal antibody OKT3 specific for the CD3 complex associated with the T cell antigen receptor can reverse acute rejection of human renal allografts. However, efficacy of anti-CD3 antibodies for treatment of patients with acute graft-versus-host disease after marrow transplantation has not been established. The dose-limiting side effects resulting from T cell activation induced by some anti-CD3 antibodies in vivo have discouraged their use for this application. We now report a phase I-II study of GVHD treatment with the anti-CD3 antibody BC3, a monoclonal murine IgG2b that, unlike OKT3, does not activate T cells. Fourteen patients were treated with BC3 after progression of acute GVHD despite treatment with cyclosporine and corticosteroids, and three patients received BC3 as primary treatment for GVHD. BC3 was administered at a dose of 0.1 or 0.2 mg/kg/day for seven or eight days. Five patients achieved complete resolution of GVHD, eight patients had partial improvement, two patients had no change, and two patients had progression of GVHD on therapy. Responses were sustained in 8 of 13 patients. Mild chills, fever, hypertension, and chest discomfort occurred in various combinations following 6 of 17 (35%) initial infusions of BC3 and following 4 of 99 (4%) subsequent infusions. In each instance it was possible to continue BC3 therapy without adjusting the dose or treatment schedule. In each patient treated, the absolute count of peripheral blood lymphocytes decreased transiently but returned to baseline within 22 hr after the first infusion. Circulating T cells had surface CD3 molecules saturated by the infused antibody in all but one patient. Four patients survived longer than one year after treatment with antibody BC3, and 13 patients died of infection or organ failure. Administration of the nonmitogenic anti-CD3 antibody BC3 was associated with improvement in the clinical manifestations of GVHD with minimal acute toxicity. Efficacy of antibody treatment did not depend on depletion of circulating T cells. Therefore, antibody BC3 may be achieving therapeutic immunosuppression by modulating T cell function. Controlled studies in patients treated earlier in the course of GVHD should determine whether antibody BC3 can improve survival.

Adult↗
PubMed1992

A pilot study of low-dose cyclosporin for graft-versus-host prophylaxis in marrow transplantation.

Nineteen patients with leukaemia, preleukaemia, and aplastic anaemia were treated by marrow transplantation from HLA-identical siblings. All were given postgrafting immunosuppression with a combination of methotrexate (days 1, 3, 6 and 11) and cyclosporin (days--1 to 180). In an attempt at reducing cyclosporin-associated toxicity, we explored whether the cyclosporin dose during the first 2 weeks could be decreased by 50% (from 3.0 to 1.5 mg/kg/d intravenously) without adversely affecting the incidence, onset, and severity of acute graft-versus-host disease (GVHD) and overall survival. Results from this pilot study were compared to those of a matched cohort of 38 patients given a standard dose of 3.0 mg cyclosporin/kg/d starting on day--1. The cumulative incidence of grade II and III acute GVHD in the 'low dose' cyclosporin group was 42% compared to 51% in the 'standard dose' group (P = 0.60). Three-year survival was 63% and 54% respectively (P = 0.59). Patients receiving the reduced cyclosporin dose during the first 14 d appeared to have less hepatotoxicity, and the methotrexate and cyclosporin doses administered were closer to the doses intended per protocol. We suggest that 'low dose' cyclosporin from day--1 to day 15 postgrafting might be as effective as 'standard dose' cyclosporin during that time period for the prevention of acute GVHD.

Acute Disease↗
PubMed1992

Marrow transplantation in cancer therapy.

Issues in bone marrow transplantation were addressed. Reconstitution of hematopoietic function is achieved by autologous, syngeneic, or allogeneic bone marrow transplant. Problems related to transplants from HLA mismatched family members, and HLA matched unrelated donors were also delineated.

Bone Marrow Transplantation↗
PubMed1992

Unrelated donor marrow transplants for severe acquired aplastic anemia.

This report is divided into two parts. The first part is a retrospective analysis of 40 unrelated transplants [UD-BMT] for severe acquired aplastic anemia [SAA], performed at five transplant centers between 1981 and 1990. The second is an interim analysis of 15 UD-BMT for SAA compared with a matched cohort of 16 sibling transplants [ID-BMT] carried out since February 1989 using prospectively collected data provided by the IMUST Study Group. In the retrospective study the actuarial survival was 28% [+/- 15] with a median follow-up of 1485 [266-3890] days post BMT. Univariate analysis showed a considerable survival advantage for patients younger than 15 years at BMT [p = 0.03]. More recently patients entered in the IMUST Study showed an actuarial survival of 50% [+/- 27] for UD-BMT compared with 58% [+/- 31] for ID-BMT recipients. These data suggest that UD-BMT is a realistic option for paediatric patients with SAA. Although numbers are very small there is some indication from IMUST Study data that better patient selection and intensive BMT protocols may also improve the results of UD-BMT in young adult patients with SAA.

Adolescent↗
PubMed1991

Allogeneic marrow transplantation in patients with chronic myeloid leukemia in the chronic phase: a randomized trial of two irradiation regimens.

A randomized trial was performed to compare two regimens of total body irradiation in patients with chronic myeloid leukemia treated by allogeneic marrow transplantation while in the chronic phase. All patients received cyclophosphamide 120 mg/kg followed by total body irradiation and marrow from HLA-identical siblings. Cyclosporine and methotrexate were used for prophylaxis against acute graft-versus-host disease. Fifty-seven patients were randomized to receive 2.0 Gy fractions of irradiation daily for 6 days and 59 were randomized to receive 2.25 Gy fractions daily for 7 days. The probabilities of relapse at 4 years were 0.25 for the 12.0 Gy group and 0.00 for the 15.75 Gy group (P = .008). The actuarial probabilities of survival and relapse-free survival at 4 years were 0.60 and 0.58 among the patients who received 12.0 Gy compared with 0.66 and 0.66 for those who received 15.75 Gy. The 4-year probabilities of transplant-related mortality were 0.24 and 0.34 respectively (P = .13) while the probability of moderate to severe acute graft-versus-host disease was 0.33 for the 12.0 Gy group and 0.44 for the 15.75 Gy group (P = .15). The lower relapse probability in the patients receiving the higher dose of total body irradiation did not result in improved survival because mortality from causes other than relapse was increased.

Adult↗
PubMed1991

Marrow transplantation from HLA-matched unrelated donors for treatment of hematologic malignancies.

Less than 40% of the patients who could benefit from marrow transplantation have an HLA-matched relative who can serve as a donor. For this reason, several centers have explored marrow transplantation from other categories of donors. This retrospective study analyzes the results of marrow transplantation for 52 patients receiving grafts from HLA-A,B,DR,Dw-phenotypically matched, MLC-compatible, unrelated volunteer donors compared to a disease, disease-stage, and age-matched cohort of 104 patients transplanted from HLA-genotypically identical sibling donors. The patients transplanted from unrelated donors had an increased incidence of grade II-IV acute graft-versus-host disease compared to patients transplanted from related donors (79% vs. 36%, P much less than 0.001). However, the probability of relapse-free survival appears similar in the two groups (P = 0.39 over all, with estimates of 41% vs. 46% at 1 year). We conclude from this preliminary data that marrow transplantation from HLA-matched unrelated donors should be considered in most, if not all, circumstances where transplantation from an HLA-matched sibling would be indicated if such a donor were available.

Acute Disease↗
PubMed1991

Allogeneic bone marrow transplantation for patients with hematologic malignancies.

Allogeneic marrow transplantation is an effective modality for the treatment of patients with hematologic malignancies. Limitations of success are donor availability, posttransplant relapses, and transplant-related morbidity and mortality. Progress is being made in improving the results of partially HLA matched family member donor transplants and in the use of HLA matched unrelated donors. Increases in dose intensity of pretransplant regimens are limited by toxicity and in order to be effective methods need to be developed to ameliorate side effects. The use of anti-inflammatory agents and recombinant growth factors show promise in decreasing transplant-related deaths.

Animals↗
PubMed1991

Treatment of adult acute lymphoblastic leukemia with allogeneic bone marrow transplantation. Multivariate analysis of factors affecting acute graft-versus-host disease, relapse, and relapse-free survival.

Between February 1972 and December 1987, 192 adults (greater than or equal to 18 years old) with acute lymphoblastic leukemia were transplanted using genotypically HLA-identical marrow donors. Median patient age was 23 years. Eighty-nine patients were in marrow remission and 103 were in relapse. Conditioning regimens included chemotherapy alone (three patients) or in combination with 9.2-17.5 Gy total body irradiation (189 patients). Graft-versus-host disease (GVHD) prophylaxis consisted of methotrexate and/or cyclosporine. Seventy-nine patients developed grades II-IV acute GVHD and 28 of 122 patients who survived at least 100 days developed chronic GVHD. Relapse-free survival at 5 years was 21% for patients transplanted in first remission, 15% for those in greater than or equal to 2nd remission, and 12% for those transplanted in relapse. Patient and donor characteristics were evaluated in multivariate analyses for their effect on development of acute GVHD, survival, relapse, and relapse-free survival. An increased risk of developing acute GVHD was associated with increasing donor age. Variables significantly associated with both increased survival and relapse-free survival included transplantation in first remission, younger patient age, and not developing interstitial pneumonia. A decreased probability of relapse was associated with transplantation in first remission, male patient sex, and grades II-IV acute GVHD.

Acute Disease↗