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Biomedical subjects

A D Hess

Publications and source records attributed to A D Hess.

9 recordsLinked to original sources
PubMed1992

Induction of cutaneous graft-versus-host disease by administration of cyclosporine to patients undergoing autologous bone marrow transplantation for acute myeloid leukemia.

Cutaneous graft-versus-host disease (GVHD) has been reported after administration of cyclosporine (CSP) after autologous bone marrow transplantation (ABMT) with unpurged marrow in patients with lymphoma. To determine whether GVHD can be induced after ABMT with chemopurged marrow in acute myeloid leukemia (AML), we administered intravenous CSP for 28 days (beginning on the day of ABMT) to 19 patients with AML (12 in first remission [CR1], six in CR2, and one in CR3) who received busulfan (16 mg/kg) and cyclophosphamide (200 mg/kg) and ABMT with 4-hydroperoxycyclophosphamide (4HC)-treated marrow. In this dose-escalation trial, CSP daily doses were 1 mg/kg in seven patients, 2.5 mg/kg in eight patients, or 3.75 mg/kg in four patients. Skin biopsies were obtained weekly after ABMT or on appearance of rash and were graded for GVH changes. Overall, 15 of 19 patients (79%) had cutaneous histopathologic grade 2 GVHD at a median of 33 days (range, 14 to 49) after ABMT; in 10, cutaneous manifestations were present at time of positive biopsy. The frequency, time to onset, and duration of GVHD were similar among the three CSP dosage groups. No patients had hepatic or gastrointestinal dysfunction attributable to GVHD or required specific therapy for GVHD. Positive biopsies for GVHD were seen in seven of eight patients who received full-course, full-dose CSP and 8 of 11 patients who had CSP discontinued or dosage reduced because of renal insufficiency. Three patients (one with positive biopsy) died with ABMT-related complications. Seven patients (four CR1, three CR2) relapsed with AML at a median of 411 days (range, 178 to 549) after ABMT; six of seven had positive biopsies for cutaneous GVHD. Nine patients (seven CR1, one CR2, and one CR3) are alive without relapse at a median of 501+ days (range, 252+ to 811+) after ABMT; eight of nine had cutaneous GVHD. Short-course CSP can induce autologous GVHD in recipients of chemopurged marrow autografts for AML, but randomized prospective trials are needed to determine whether this immunologic reaction is associated with alterations in leukemic relapse rate and disease-free survival after ABMT in AML.

Adolescent↗
PubMed1992

Thalidomide for the treatment of chronic graft-versus-host disease.

BACKGROUND: Allogeneic bone marrow transplantation is an accepted therapy for hematologic cancer, aplastic anemia, and inherited immunodeficiencies. Chronic graft-versus-host disease (GVHD) is the principal complication in patients surviving more than 100 days. Thalidomide has been shown experimentally to be effective in treating GVHD. METHODS: We treated 23 patients with chronic GVHD refractory to conventional treatment and 21 patients with "high-risk" chronic GVHD (identified as having at least two of the following three risk factors: chronic GVHD that has evolved from acute GVHD, lichenoid skin or mucous-membrane changes, and hepatic dysfunction. Such patients have a high mortality rate.) with thalidomide in a dose that produced a plasma level of 5 micrograms per milliliter two hours after administration. Therapy was continued for three months after a complete response or for six months after a partial response. RESULTS: The overall actuarial survival of all enrolled patients was 64 percent. Survival was 76 percent among the patients receiving salvage therapy for refractory GVHD and 48 percent among those with high-risk GVHD. A complete response was observed in 14 patients, a partial response in 12 patients, and no response in 18. Side effects were minor, most notably sedation in almost all patients. CONCLUSIONS: In this preliminary trial, thalidomide appeared to be safe and effective for the treatment of chronic GVHD. A trial comparing thalidomide with prednisone in patients with newly diagnosed chronic GVHD will be required to demonstrate its relative efficacy.

Adolescent↗
PubMed1992

Autologous graft-versus-host disease: a novel approach for antitumor immunotherapy.

Autologous bone marrow transplantation (BMT) is a therapeutic option for the treatment of lymphohematopoietic malignancies and solid tumors. Despite the intensive cytoreductive therapy, however, the rates of tumor recurrence after autologous BMT remain unacceptably high. Current studies suggest that the administration of cyclosporine (CsA) disrupts the reconstitution of self-tolerance following autologous BMT leading to the induction of an autoimmune graft-versus-host disease (GVHD). Studies in a rat tumor model and preliminary clinical trials suggest that this autoimmune or autologous GVHD provides a significant antitumor effect. Moreover, the antitumor effect of autologous GVHD can be enhanced by administration of gamma-interferon, which upregulates the antigen recognized by the autoreactive effector cells of autologous GVHD. These studies indicate that the induction of an autoimmune GVHD after autologous BMT may be a promising immunotherapeutic approach for treatment of certain neoplastic diseases.

Animals↗
PubMed1992

Interferon-gamma potentiates the antitumor effect of cyclosporine-induced autoimmunity.

Graft-versus-host-disease (GVHD), which results after allogeneic bone marrow transplantation (BMT), is associated with reduced leukemic relapse. This may be mediated by an immunologic attack with subsequent destruction of residual tumor cells. On the other hand, GVHD does not normally occur after autologous BMT (ABMT), which has an inherently high relapse rate. However, an autoimmune syndrome (AIS) similar to GVHD can be induced after autologous/syngeneic BMT by administration of cyclosporine-A (CsA), resulting in the production of major histocompatibility complex (MHC) class II or Ia autoreactive cytolytic effector cells. Since many hematopoietic malignancies express variable levels of class II molecules, we hypothesized that the adjuvant use of interferon-gamma (IFN-gamma) with CsA-induced autoimmunity after autologous/syngeneic BMT may upregulate class II antigens on residual tumor cells and make them more susceptible to attack by the Ia-reactive cells of CsA-induced AIS. The present studies demonstrated that the CsA-induced autoimmune syndrome mediated an anti-tumor effect, although this effect was dependent on challenge with a minimal number of tumor cells. Further studies clearly demonstrated that the antitumor effect could be markedly enhanced by administration of IFN-gamma which increased the susceptibility of the tumor to recognition and lysis by the CsA induced autoimmune effector cells. The induction of MHC class II-restricted AIS similar to GVHD by administration of CsA together with the ability to manipulate the surface phenotype of residual tumor cells may lead to decreased relapse rates in the ABMT setting.

Animals↗
PubMed1991

The effect of the CD28 activation pathway on the immunosuppressive action of cyclosporine.

The effect of the CD28 activation pathway on the immunosuppressive action of CsA was assessed. Human peripheral blood lymphocytes were stimulated with anti-CD3, bryostatin (Bryo) a novel activator of protein kinase C (PKC) and anti-CD28 singly or in combination, to which graded doses of CsA were added to determine relative sensitivity. Proliferation, IL-2 production, and IL-2 receptor expression were assessed and the IC50 determined. Lymphocytes stimulated with Bryo exhibited a marginal proliferative response but expressed the IL-2 receptor despite the presence of CsA. Addition of anti-CD3 or anti-CD28 to Bryo-stimulated lymphocytes promoted a vigorous proliferative response. CsA effectively inhibited the proliferative response and IL-2 production induced with anti-CD3 and Bryo but did not inhibit the response of cells stimulated with anti-CD28 and Bryo. However, II-2 receptor expression in both sets of cultures were comparable due to the induction of IL-2 receptor by Bryo and was not inhibited by CsA. Costimulation of lymphocytes with anti-CD3 plus anti-CD28 resulted in a 2-3-fold enhancement of proliferation compared with lymphocytes stimulated with anti-CD3 alone. Addition of CsA to lymphocytes stimulated with anti-CD3 resulted in the dose-dependent suppression of the proliferative response and IL-2 production (IC50 = 10-25 nM) but less so for IL-2 receptor expression (IC50 = 100-150 nM). In comparison, the proliferative response and IL-2 production elicited by anti-CD3 + anti-CD28 was more resistant to the effects of CsA (IC50 = 100-200 nM). However, IL-2 receptor expression exhibited comparable sensitivity to CsA (IC50 = 100-200 nM) in the presence of anti-CD28. Combination drug:drug studies revealed that CsA and the protein kinase C inhibitor H-7 were additive for both anti-CD3 and anti-CD3 plus anti-CD28 response. On the other hand, the cGMP-dependent protein kinase inhibitor H-8 was synergistic with CsA in inhibiting the response of lymphocytes to anti-CD3 plus anti-CD28 but only additive for responses to anti-CD3. Taken together, these data suggest that CsA inhibits T cell activation at two distinct levels, leading to inhibition of IL-2 production and inhibition of IL-2 receptor expression. Activation of the CD28 pathway partially overcomes the inhibitory activity of CsA on IL-2 production and may be mediated by indirect activation of a cGMP-dependent protein kinase.(ABSTRACT TRUNCATED AT 400 WORDS)

1-(5-Isoquinolinesulfonyl)-2-Methylpiperazine↗
PubMed1979

Isolation and characterization of canine venereal tumor-associated inhibitory and blocking factors.

Spontaneous regression of the canine venereal tumor is associated with the production of a serum factor which inhibits in vitro tumor colony-forming units in agar. Logarithmic or persistent tumor growth, on the other hand, is characterized by a serum factor which protects cells against in vitro inhibition (blocking factor). These factors have been characterized by immunochemical methods. Whole regressor and blocking sera were fractionated by Sephadex G-200 filtration and immunoabsorption with rabbit antiserum specific for canine immunoglobulin G2a. Fractions were characterized by immunoelectrophoresis, radial immunodiffusion, and disc gel electrophoresis. In vitro inhibitory and blocking activity of the whole serum was accounted for by the purified immunoglobulin G2a. Blocking activity was also found in protein eluted from logarithmically growing tumors. Preparative polyacrylamide electrophoresis revealed five major fractions with blocking activity only in the immunoglobulin G fraction. Tumor eluates and immunoglobulin G isolated from serially removed tumors demonstrated with the clinical course of the tumor. Using ultrafiltration and sodium dodecyl sulfate electrophoresis of tumor-associated immunoglobulin G at low pH, it was not possible to identify an antigen complexed to the blocking antibody.

Animals↗
PubMed1977

Intralesional Bacillus Calmette-Guérin immunotherapy of canine venereal tumors.

Canine transmissible venereal tumors were studied for response to intralesional Bacillus Calmette-Guérin (BCG) therapy. Six pairs of littermates, identical for the major histocompatibility complex, were evaluated. One member of each pair received intralesional BCG to one of two growing tumors. Lesions of control animals received 0.9% NaCl solution. Both injected and noninjected lesions of BCG-treated animals underwent regression within 63 days, as compared to an extended period of tumor growth (beyond 100 days) for controls (p less than 0.05). Serial in vitro assays during therapy included; (a) mixed lymphocyte-tumor culture, (b) phytohemagglutinin stimulation, and (c) assessment of lymphocyte surface markers. Lymphocytes from BCG-treated dogs were significantly more responsive to tumor cells in mixed lymphocyte-tumor culture assay than were those from controls (p less than 0.05). Maximal responses occurred during tumor regression. T- and B-lymphocyte levels as assayed by rosette formation and surface marker immunoglobulins were not influenced by BCG therapy. It was concluded that intralesional BCG therapy of canine venereal tumors was highly effective in causing regression of injected and noninjected lesions. This tumor model system may be useful for the evaluation of the effectiveness of new immunotherapeutic approaches on established neoplasms in large, randomly bred animals.

Animals↗