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Biomedical subjects

G D Marshall

Publications and source records attributed to G D Marshall.

At least 37 records · Page 2Linked to original sources
PubMed1995

Decreased CD3-mediated interferon-gamma production in relapsing-remitting multiple sclerosis.

Multiple sclerosis (MS) is a chronic inflammatory disease of the central nervous system that has been postulated to be T-cell mediated. We examined the proliferation and cytokine secretion of mononuclear cells after stimulation with OKT3 (anti-CD3) monoclonal antibody concanavalin A, or ionomycin plus myristic acid palmityl ester in subjects with stable relapsing-remitting MS. Control subjects demonstrated good proliferation to anti-CD3 monoclonal antibody whereas subjects with relapsing-remitting MS showed a significantly decreased anti-CD3 monoclonal antibody-mediated response. There was no difference in concanavalin or ionomycin plus myristic acid palmityl ester stimulation between control subjects and MS subjects. Secretion of interferon-gamma was significantly decreased and transforming growth factor-beta was significantly increased from cultures stimulated with anti-CD3 monoclonal antibody, but not ionomycin plus myristic acid palmityl ester or concanavalin A, in MS patients compared to control subjects. Secretion of interleukin-10 and tumor necrosis factor-alpha was not different between control subjects and MS patients following stimulation with anti-CD3 monoclonal antibody, concanavalin A, or ionomycin plus myristic acid palmityl ester, or of interleukin-2 and interleukin-4 following stimulation with anti-CD3 monoclonal antibody or concanavalin A. An abnormality of signal transduction and secretion of the immunomodulatory molecule interferon-gamma may exist in MS via the CD3 T-cell receptor complex.

CD3 Complex↗
PubMed1991

Smoking cessation for substance abuse inpatients.

The impact of a smoking cessation program on substance abuse inpatients was investigated. Thirty-nine male veterans were randomly assigned to stop-smoking (n = 19) or wait-list conditions (n = 20), and followed up 3- and 6-months postdischarge. Compared to wait-list subjects, stop-smoking subjects were more likely to continue inpatient treatment at least 30 days following study enrollment and reported greater posttreatment reductions in cigarette nicotine delivery. Importantly, assessments of postdischarge substance use and hospital readmission rates did not reveal any adverse effects from participation in the stop-smoking program.

Adult↗
PubMed1991

Comparison of three pretreatment protocols to prevent anaphylactoid reactions to radiocontrast media.

Three pretreatment regimens were compared for prevention of anaphylactoid reactions in 149 patients who previously had reacted to radiocontrast media (RCM) administration. From 1976 to 1980, 52 patients were treated with 50 mg of oral prednisone 13, 7, and 1 hour before and 50 mg intramuscular diphenhydramine 1 hour before procedures (group I). From 1980 to 1984, 48 patients received 300 mg oral cimetidine one hour before procedure in addition to the other regimen (group II). From 1984 to 1989, 49 patients received the three drugs and 25 mg oral ephedrine one hour before procedures (group III). Previous reactions were similar in each group, consisting of urticaria and/or angioedema in all patients, hypotension in some (groups I, 5; II, 6; III, 4), and wheezing in two (group I). Readministration of RCM was intraarterial (groups I, 18; II, 20; III, 20) or intravenous. Generalized reactions upon readministration of RCM occurred in 4 (8%) of group I and 3 (6%) of both groups II and III. All reactions consisted of urticaria and/or angioedema, were mild, and required no specific treatment. In a separate group of ten patients whose previous reactions to RCM were life threatening (shock), pretreatment was accompanied by a provocative dosing regimen. Two patients (20%) experienced systemic reactions that resulted in termination of the procedure. All our pretreatment regimens were equally effective; however, we favor a more comprehensive pretreatment protocol (regimen III) based upon our lack of demonstrated adverse effects and a possible therapeutic advantage as reported by other investigators.(ABSTRACT TRUNCATED AT 250 WORDS)

Administration, Oral↗
PubMed1989

Preparation and analysis of bifunctional immunoconjugates containing monoclonal antibodies OKT3 and BABR1.

OKT3 and BABR1 [anti-(breast tumour) antibody] were conjugated using N-succinimidyl-3-(2-pyridy]dithio)propionate (SPDP). The procedure employed mild reducing conditions for SPDP-BABR1 and short conjugation incubations at 37 degrees C. The bifunctional immunoconjugates thus produced were isolated by HPLC gel filtration on a preparative TSK 3000 SW column. Both intact IgG and F(ab')2 fragments have been conjugated. The ratio of SPDP to IgG for the optimal yield of dimeric OKT3-BABR1 heteroconjugates was determined to be 2 for OKT3 and 1-2 for BABR1. The OKT3-BABR1 dimers were shown to be bifunctional heteroconjugates by polyacrylamide gel electrophoresis, isoelectric focusing, radial immunodiffusion, and flow cytometry. The binding specificities of the bifunctional heteroconjugates were identical to the specificities of both parent antibodies.

Antibodies, Monoclonal↗
PubMed1989

Multiple cycles of constant infusion recombinant interleukin-2 in adoptive cellular therapy of metastatic renal carcinoma.

Twenty patients were treated with metastatic renal cell cancer with 5-day cycles of constant infusion recombinant interleukin-2 (rIL-2) at 3 X 10(6) U/m2/day and with infusion of in vitro activated autologous mononuclear cells. The initial eight patients completed all rIL-2 and cellular therapy in a single 25-day treatment period. The subsequent 12 patients entered a 6-month treatment program involving two separate 15-day cycles of cellular therapy followed by four monthly cycles of maintenance rIL-2. Among eight patients in the 25-day treatment program, there were two with partial response (PR) and one with minor response (MR). None of these responses exceeded 2 months in duration. Among the 12 patients undergoing recycling of therapy, there were two with complete response (CR), two with PR, and one with MR. All four patients with CR or PR in this group demonstrated continuing response with recycling of treatment and none relapsed while receiving maintenance interleukin-2. Three remain in remission at 10, 11, and 12 months. These pilot data confirm that patients can tolerate multiple cycles of adoptive immunotherapy involving constant infusion rIL-2 and suggest that recycling of therapy is necessary to achieve clinically meaningful results.

Adult↗
PubMed1988

Principles of biotherapy and its application to the treatment of disseminated renal cancer.

Monoclonal antibody technology permits the preparation of tumor-specific immunoglobulin reagents that can be used directly in tumor therapy or that can be coupled to various chemotherapeutic drugs or toxins to aid in their delivery to the tumor site and thus enhance their therapeutic effectiveness. Additionally, recombinant DNA technology has facilitated the economic production of rare lymphokines (e.g., interleukin 2, interferon alpha and interferon gamma) or cytokines (tumor necrosis factor, lymphotoxin) that can either modulate the host immune response or kill tumor cells, respectively. These developments collectively have led to the development of a fourth modality for treatment of human cancers--biotherapy--as an addition to surgery, radiation, and chemotherapy modalities. This paper presents the rationale and emerging practice of the biotherapy of cancer and documents early clinical results, including the treatment of metastatic renal carcinoma at the Biological Therapy Institute.

Animals↗
PubMed1987

Constant-infusion recombinant interleukin-2 in adoptive immunotherapy of advanced cancer.

Adoptive immunotherapy involving bolus-dose recombinant interleukin-2 (rIL-2) has been reported to induce tumor regression in some patients with cancer, but has been associated with severe fluid retention and cardiopulmonary stress. In an effort to preserve the efficacy but reduce the toxicity of this treatment, we used escalating doses of rIL-2 as a constant infusion rather than as a bolus dose. Forty-eight patients with advanced cancer received rIL-2 as a 24-hour infusion in five-day cycles separated by five-day periods of rest and leukapheresis. Eight patients were removed from the study before receiving cells activated in vitro. In the 40 who could be evaluated for their response, there were 13 partial responses (32.5 percent) and 2 minor responses. Partial responses were observed in Hodgkin's disease (one of one), non-Hodgkin's lymphoma (one of one), lung cancer (one of five), ovarian cancer (one of one), parotid cancer (one of two), renal cancer (three of six), and melanoma (five of ten). Responses were associated with a good performance status, a base-line lymphocyte count above 1400 per cubic millimeter, and an rIL-2-induced lymphocyte count of at least 6000. Optimal lymphocytosis required a priming dose of rIL-2 of 3 X 10(6) U per square meter of body-surface area per day, and 15 of 28 patients receiving this priming dose responded to treatment. A weight gain of more than 10 percent of total body weight (five patients) and dyspnea at rest (six patients) were unusual events restricted to patients with poorer pretreatment performance. We conclude that the administration of rIL-2 as a constant infusion may preserve the antineoplastic activity of adoptive immunotherapy while increasing the safety and comfort of patients.

Adult↗
PubMed1982

Planning recruitment.

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Clinical Trials as Topic↗
PubMed1981

In vivo generation of suppressor T cells by thymosin in congenitally athymic nude mice.

Treatment of nude mice with thymic factors such as thymosin has been mostly ineffective in generating effector T cells. This study examined the effects of treating nude mice with thymosin fraction 5 on the induction of cells that could participate in and/or regulate cytotoxic T lymphocyte (CTL) generation by normal spleen cells in vitro. Splenic lymphocytes from BALB/c nude mice injected with thymosin fraction 5 every other day for 2 wk were tested for their ability to generate CTL in vitro. Two days after the last subcutaneous injection of thymosin, nude spleens were removed, mixed with normal BALB/c spleen cells, and placed into a mixed lymphocyte tumor culture (MLTC) against allogeneic RBL 5 tumor cells. After a 5-day incubation, cultures were tested for the presence of CTL in a 4-hr 51Cr-release assay. Spleen cells from thymosin-treated nude mice did not generate CTL but suppressed the ability of normal spleen cells to generate CTL in vitro. Characterization of the thymosin-induced nude mouse suppressor cells showed them to be Thy 1 positive, nonadherent, cyclophosphamide-sensitive T cells. These data demonstrate that some T cell maturation occurs in vivo under thymosin influence. However, the activity of these cells is initially limited to a regulatory function. These studies suggest that maturation of functional suppressor T cells occurs before CTL. Further immunologic manipulation appears to be necessary in order to induce CTL effector cells in nude mice.

Animals↗
PubMed1980

Thymosin: basic properties and clinical application in the treatment of immunodeficiency diseases and cancer.

Thymosin fraction 5 contains a family of polypeptides with varying biological activities. Current efforts in the thymosin research program are involved in further chemical characterization of thymosin peptides and evaluation of clinical immunotherapeutic protocols. Recent clinical studies with thymosin fraction 5 have shown therapeutic potentials for treatment of patients with primary immunodeficiency diseases and cancer.

Cyclic GMP↗
PubMed1980

Regulation of in vitro generation of cell-mediated cytotoxicity. II. Characterization of thymosin-induced suppressor T cells.

Thymosin fraction 5 can induce the appearance of suppressor T cells capable of regulating the in vitro generation of cytotoxic T lymphocytes (CTL) in a 5-day allogeneic or syngeneic mixed lymphocyte-tumor culture (MLTC). Characterization of the suppressor cell population demonstrated it to be a nonadherent, cyclophosphamide-sensitive T cell. In addition, adult thymectomy (Tx) eliminated suppressor cell precursors in spleen, pointing to a direct thymic dependence of the population. Kinetic studies showed that the thymosin influence was necessary for at least the first 12 hr of culture in order for optimal suppression to occur. The in vitro-generated suppressor T cells were antigen specific and could be generated with spleen, thymus, or lymph node cell preparations, suggesting the widespread existence of a regulatory T-cell population under direct humoral thymic control.

Animals↗
PubMed1979

Current status of thymosin research: evidence for the existence of a family of thymic factors that control T-cell maturation.

Thymosin fraction 5 contains several distinct hormonal-like factors which are effective in partially or fully inducing and maintaining immune function. Several of the peptide components of fraction 5 have been purified, sequenced and studied in assay systems designed to measure T-cell differentiation and function. These studied indicate that a number of the purified peptides act on different subpopulations of T-cells (see Figure 1). Thymosin beta 3 and beta 4 peptides act on terminal deoxynucleotidyl transferase (TdT) negative precursor T-cells to induce TdT positive cells. Thymosin alpha 1 induces the formation of functional helper cells and conversion of Lyt- cells to Lyt 1+, 2+, 3+ cells. Thymosin alpha 7 induces the formation of functional suppressor T-cells and also converts Lyt- cells to Lyt 1+, 2+, 3+ cells. These studies have provided further evidence that the thymus secretes a family of distinct peptides which act at various sites of the maturation sequence of T-cells to induce and maintain immune function. Phase I and Phase II clinical studied with thymosin in the treatment of primary immunodeficiency diseases, autoimmune diseases, and cancer point to a major role of the endocrine thymus in the maintenance of immune balance and in the treatment of diseases characterized by thymic malfunction. It is becoming increasingly clear that immunological maturation is a process involving a complex number of steps and that a single factor initiating a single cellular event might not be reflected in any meaningful immune reconstitution unless it is the only peptide lacking. Given the complexity of the maturation sequence of T-cells and the increasing numbers of T-cell subpopulations that are being identified, it would be surprising if a single thymic factor could control all of the steps and populations involved. Rather, it would appear that the control of T-cell maturation and function involves a complex number of thymic-specific factors and other molecules that rigidly control the intermediary steps in the differentiation process.

Amino Acid Sequence↗
PubMed1978

Overview of thymosin activity.

Our current research program centers around the biologic and chemical characterization of the family of polypeptides present in thymosin fraction 5. A system of nomenclature has been developed and the peptides are being systematically isolated and chemically characterized. Thymosin fraction 5 and its component parts influence a variety of lymphocyte properties including cyclic nucleotide levels, migration inhibitory factor production, T-dependent antibody production, and expression of certain surface markers. Thymosin is being used in clinical trials to investigate its effects on immunodeficiency diseases, malignant diseases, and autoimmune diseases.

Animals↗