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Biomedical subjects

M S Mitchell

Publications and source records attributed to M S Mitchell.

At least 91 records · Page 5Linked to original sources
PubMed1985

Cytotoxic activity of human pulmonary alveolar macrophages.

The functions of human pulmonary alveolar macrophages (PAMs) have been relatively little studied compared with those of their circulating counterparts, blood monocytes. This study examined the ability of human PAMs to kill primary human tumor cell cultures and control normal fibroblasts in vitro. PAMs were derived by bronchial lavage from patients with lung cancer of various histological types and stages, patients with acute or chronic noncancerous pulmonary disorders, and subjects with a presumed illness who proved to be normal. After extensive washing, the PAMs were cocultured with [3H]proline-labeled tumor cells, principally lung cancers and melanomas, at various effector:target ratios for 60 hr. Cytotoxicity was measured by comparing radioactivity associated with the remaining adherent tumor cells cultured in the presence or absence of PAMs. Twenty-eight of 42 preparations of PAMs from 42 individuals were cytotoxic to one or more short-term primary tumor cultures. All 28 specimens from patients with lung cancer or chronic pulmonary disease were cytotoxic; all of the 14 PAM preparations lacking cytotoxicity were from individuals with acute pulmonary disorders or who were proved free of pulmonary disease. PAMs were cytotoxic even at effector:target ratios of 2.5:1 or 1.25:1. Fibroblasts were unaffected at any ratio. Sarcoidosis patients in remission had noncytotoxic PAMs, whereas the disease in relapse was characterized by cytotoxic PAMs. Serial study of 2 patients confirmed a loss of reactivity during remission. Smoking did not correlate with the presence or absence of spontaneous cytotoxicity and did not influence the degree of cytotoxicity in "reactors." Partially purified alpha-interferon enhanced the killing of cytotoxic PAMs in 10 of 21 instances but did not induce cytotoxicity in 9 tests on nonreactive PAMs. We conclude that human PAMs from patients with lung cancer or chronic pulmonary diseases, including active sarcoidosis, were cytotoxic to several recently explanted tumor cell cultures. PAMs from acute pulmonary dysfunctions and those from patients with inactive sarcoidosis were not spontaneously cytotoxic.

Adenocarcinoma↗
PubMed1984

Kaposi's sarcoma and autoimmune thrombocytopenia.

Outbreaks of Kaposi's sarcoma, opportunistic infections, and autoimmune thrombocytopenia among homosexual men have recently been described. We report here a case with the combination of Kaposi's sarcoma and autoimmune thrombocytopenia. Our patient presented with Kaposi's sarcoma limited to the integument and autoimmune thrombocytopenia diagnosed by elevated platelet bound IgG. Characteristics of immunosuppression included lymphocytopenia and a reversed blood helper:suppressor T lymphocyte ratio. Immunohistochemical evaluation of skin biopsy specimens revealed tumor cells to contain Factor VIII-related antigen (a vascular endothelial cell marker). In addition some tumor cells stained positively with a monoclonal antibody directed against a cytomegalovirus antigen.

Adult↗
PubMed1984

Staphylococcal protein A immunoadsorptive column induces mitogenicity in perfused plasma.

A Phase I trial of therapy with the staphylococcal protein A immunoadsorptive column was conducted in six patients with advanced breast or brain cancer. Four of the patients reacted strongly to the therapy with high fever, chills, and rigors. The plasma of these four patients after perfusion over the column was strongly mitogenic to normal lymphocytes. This mitogenicity apparently was dependent on the amount of protein A on the matrix; small attached doses caused mitogenicity, while higher doses also induced clinical symptoms. Mitogenicity was not due to protein A leached from the column, as determined by heat-inactivation experiments. From these data it appears likely that the mitogenic plasma component generated by perfusion of the plasma over a protein A matrix is responsible, at least in part, for the immunomodulatory activity of the staphylococcal protein A immunoadsorptive column.

Astrocytoma↗
PubMed1984

Regional isolated perfusion of high risk melanoma of the extremities with imidazole carboxamide.

Twenty-four patients have been treated by regional isolated perfusion with decarbazine for melanoma of an extremity, with a follow-up period of seven to 72 months. None of these patients had any signs or symptoms of toxicity from the drug. The serum glutamic-oxalacetic transaminase level was elevated by the first postoperative day and returned to normal within the next six days. Fourteen of these 24 patients are free of disease for a follow-up period of 23 to 70 months. Three of the seven patients treated for local or intransit metastases are free of disease for five, 60 and 61 months; a fourth patient had subcutaneous metastases of the trunk develop while remaining disease-free in the perfused extremity for 72 months, and a fifth patient perfused for numerous intransit metastases of a leg had resolution of many of the nodules and remains without new lesions for nine months. Decarbazine is recommended as a safe and valuable drug for the perfusion of extremities with melanoma.

Arm↗
PubMed1984

Thymidylate synthetase inhibition in malignant tumors and normal liver of patients given intravenous 5-fluorouracil.

Single surgical biopsies of solid tumor were obtained at 20 to 240 min after drug administration in 21 patients given first-dose bolus i.v. 5-fluorouracil (5-FUra), 500 mg/sq m, and assayed for 5-fluorodeoxyuridylate (FdUMP), deoxyuridylate (dUMP), total thymidylate synthetase (TS), and non-FdUMP-bound, free enzyme. Nineteen patients had cancer of gastrointestinal origin, 13 of these colorectal, and 2 patients had breast adenocarcinoma. In 9 patients, synchronous biopsies of surgically normal liver were obtained along with samples of hepatic tumors metastatic from gastrointestinal sites. Total TS averaged 4.18 pmol/g in the malignant tissues and 2.23 pmol/g in liver. FdUMP levels in the gastrointestinal tumors were higher than in normal liver, were highest at the earliest time interval studied, 20 to 30 min, and appeared to decrease exponentially through 120 min. TS inhibition averaged 70 to 80% in gastrointestinal tumor biopsies and less than 50% in normal liver. Levels of dUMP were low and varied little with time. Those gastrointestinal tumors with higher FdUMP:dUMP ratios showed significantly greater TS inhibition. Tumors of 3 patients who benefited from 5-FUra therapy (1 patient with colonic adenocarcinoma and the 2 patients with breast adenocarcinoma) showed greater TS inhibition than did tumors of remaining patients. It is concluded that the apparent time course changes observed in FdUMP, dUMP, and TS in the grouped data are qualitatively similar to findings of murine studies in vivo and that the relationship between FdUMP:dUMP ratios and TS inhibition are consistent with established in vitro enzymic kinetics. Thus, biopsies of tumors at short time periods after 5-FUra administration may be usefully studied for biochemical parameters of TS inhibition, with the objectives of correlation of sensitivity to subsequent 5-FUra therapy and clarification of mechanisms of drug resistance.

Adult↗
PubMed1983

Breast cancer treatment--current status. 4. Adjuvant therapy.

Adjuvant chemotherapy of early breast cancer in premenopausal women has nearly reached the point where it can be said with confidence that the relapse-free survival rate, as well as overall survival rate, is being lengthened, especially when drug combinations are used. In postmenopausal women, however, adjuvant chemotherapy has not consistently improved the relapse-free rate. Some investigators have postulated that postmenopausal patients do not respond as well to chemotherapy as their premenopausal counterparts because they usually receive lower doses. Thus, trials of these drugs at doses that more closely approximate the calculated dose are needed in postmenopausal patients. Recent advances in determination of estrogen and progesterone receptors in breast cancer cells have allowed effective use of adjuvant hormone therapy instead of or in addition to chemotherapy in some patients with early disease. However, further investigation of the role of hormone manipulation in breast cancer is also needed. Adjuvant chemotherapy of advanced breast cancer, however, is only palliative; duration of relapse-free and overall survival is not nearly as long as in early disease. Hormone therapy has been effective as initial treatment in patients with positive estrogen and/or progesterone receptors. Alternative treatments under investigation include use of new anthracycline derivatives, high-dose single agents, and biomodulation with interferon and Staphylococcus aureus protein A. Thus, while advanced breast cancer is not now curable, the wide range of effective agents and promising new approaches to treatment certainly justify some optimism for the future.

Antineoplastic Agents↗
PubMed1983

Pyran (MVE-5) reverses the inhibition of macrophage receptors for cytophilic antibody induced by soluble immune complexes.

Soluble antigen-antibody (Ag-Ab) complexes, composed of 3 M KCl-extracted leukemia L1210 antigens and antibody to L1210, given to C57B1/6 mice caused immunosuppression in the mice. This was reflected in part by (a) the inhibition of cytophilic antibody receptors on peritoneal macrophages and (b) decreased phagocytic activity of the macrophages. Pyran copolymer MVE-5 given to the mice either 4 h before, or 5 or 8 days after, the Ag-Ab complexes abrogated this suppression. Macrophages from MVE-5-treated mice attached cytophilic antibodies to L1210 to the same extent as normal macrophages, despite the concomitant or previous administration of immune complexes. Macrophages from normal or immune-complex-treated mice given MVE-5 were more phagocytic than their counterparts from groups not given MVE-5. All of these effects of MVE-5 required 3-5 days to become manifest. Thymocytes or spleen T cells from mice treated with Ag-Ab complexes adoptively transfer the suppression to normal syngeneic mice. Treatment of the mice with MVE-5 4 h before the immune complexes abrogated the ability of T cells to transfer the suppression. However, MVE-5 given 5 or 8 days after Ag-Ab complexes did not affect the adoptive transfer of suppression, even when the testing of macrophages in recipients of T cells was performed 10 days after transfer. Treatment of normal mice with MVE-5 enabled their spleen or thymus T cells to prevent, but not reverse, the inhibition of macrophages upon adoptive transfer. Thus, the transfer of T cells from MVE-5-treated mice antagonized suppression if performed 4 h before administering immune complexes, whereas such "activated" T cells were ineffective when transferred 5 or 8 days later. MVE-5 apparently prevented the generation of suppressor inducer T cells, but once generated, these cells could not be directly antagonized by MVE-5 or by T cells stimulated by this agent. MVE-5 significantly activated peritoneal macrophages in T-cell-depleted mice, as well as in normal mice. The ability to form cytophilic antibody-mediated rosettes and to kill syngeneic B16 melanoma cells were both enhanced in the T-cell-depleted mice. Pyran copolymer MVE-5 probably exerted direct effects on peritoneal macrophages and an indirect effect through T cells in overcoming the suppressive effects of Ag-Ab complexes on macrophages.

Animals↗
PubMed1983

Immunological effects of recombinant interferon-alpha 2 in cancer patients.

Fifteen patients with various types of cancer, resistant to conventional therapy, were entered into a phase I trial of pure interferon-alpha 2 (IFN-alpha 2) produced by recombinant DNA technology. Groups of patients received either 3, 10, 30, or 50 x 10(6) units (U) of IFN-alpha 2 subcutaneously daily for 4 weeks and were closely followed for possible toxicity. At the higher doses, toxicity was encountered, which led to reduction in the frequency of administration. For immunological testing, peripheral blood mononuclear cells were obtained before treatment on day 1, on day 2, and during the 2nd, 3rd, and 7th weeks of the study. The cells were tested for natural killer (NK) activity, antibody-dependent cellular cytotoxicity (ADCC), monocyte-mediated antibody-dependent cellular cytotoxicity (MMADCC), and spontaneous monocyte-mediated cytotoxicity (SMC). ADCC was augmented at all doses in 9 of 15 patients, 6 of whom exhibited elevated levels by day 2. In direct contrast, MMADCC was decreased in 12 of 14 patients 7-20 days after beginning treatment. SMC was increased on day 2 in 1 of 2 patients given 3 x 10(6) U and in 3 of 4 patients given 10 x 10(6) U. SMC in the other patients given these doses was unchanged on day 2, with no decreases noted. In contrast, SMC was decreased in 2 of 4 patients given 30 x 10(6) U. SMC in the other patients given these doses was unchanged on day 2, with no decreases noted. In contrast, SMC was decreased in 2 of 4 patients given 30 x 10(6) U and in 2 of 3 patients given 50 x 10(6) U. NK cell activity was increased in 2 of 3 patients given 3 x 10(6) U, but was either unchanged or decreased in patients given higher doses. The only exception was an increase found in a patient given 50 x 10(6) U, whose renal cell carcinoma responded significantly to treatment. Data on NK and SMC from a phase II study of breast cancer treated daily with 3 x 10(6) U IFN-alpha 2 support our phase I observations. NK-cell activity was increased on day 2 in 3 of 8 patients, and SMC increased in 2 of 8 patients. As in the phase I study, no decreases in these functions occurred. In summary, for those responses that were dose dependent, such as NK and SMC, lower doses of recombinant IFN-alpha 2 (3 x 10(6) and possibly 10 x 10(6) U) may be more effective in increasing these antitumor activities than are higher doses.

Adult↗
PubMed1982

Modulation of cell-mediated alloimmunity by BCG. II. Induction of specific, nonadherent, non-T-killer cells by BCG and alloantigen.

The cellular basis of the augmentation of cell-mediated immunity (CMI) by systemically administered BCG was investigated in C57BL/6 mice. BCG pretreatment potentiated the CMI to alloantigens as measured by a 48-hour microcytotoxicity assay (MCA) against P815Y tumor cells. The effector cell was not a T-cell, as demonstrated by its lack of sensitivity to antithymocyte serum and complement and its failure to kill in a short-term 51Cr release assay. The effector cell also was not a classical macrophage, because it was not depleted by treatment with silica. CMI as measured by the MCA was consistently depleted by magnetic separation after incubation with carbonyl iron. The active cell(s) showed variable adherence properties. The augmentation of alloimmunity was alloantigen-specific. The specificity appeared to be due to the interaction between effector cells without inherent specificity and sensitized T-cells.

Animals↗
PubMed1982

Modulation of cell-mediated alloimmunity by BCG. I. Antagonism and potentiation of immunosuppression caused by cytarabine.

The ability of iv administered BCG to antagonize immunosuppression caused by injection of the antimetabolite cytarabine (beta-cytosine arabinoside; ara-C) was investigated in C57BL/6 mice. Treatment with BCG 10 days before alloimmunization with killed L1210 tumor cells decreased spleen T-cell-mediated cytolysis against allogeneic P815Y tumor cells, as measured by a short-term 51Cr release assay, and potentiated immunosuppression due to ara-C. In contrast, spleen cell-mediated immunity (CMI) that was assayed by a 48-hour microcytotoxicity assay (MCA) was augmented by systemic BCG administered before alloimmunization. Pretreatment with BCG resulted in a complete and long-lasting protection against the immunosuppressive effects of ara-C on this CMI as measured by the MCA. Treatment with BCG after cytoreductive therapy resulted in a significant, although transient, reversal of immunosuppression. Depending on the type of response and thus the type of effector cell measured, BCG acts as a moderate immunosuppressive agent or a strong immunopotentiator of CMI.

Animals↗
PubMed1982

Intralymphatic and regional surgical adjuvant immunotherapy in high-risk melanoma of the extremities.

A prospective, controlled study of surgical adjuvant immunotherapy with intralymphatic methanol-extractable residue (MER) of bacillus Calmette-Guerin (BCG) is preliminarily reported in 25 consecutive patients with high-risk malignant melanoma of the extremities. Patients were allocated on a random basis to receive preoperative intralymphatic immunotherapy with MER-BCG, surgical excision with regional lymphadenectomy and intraoperative infiltration of MER-BCG, and postoperative monthly intradermal vaccinations with BCG; or surgery and lymphadenectomy alone. Twenty patients followed for more than 1 year are the basis of this report. Fifteen patients accepted randomization, whereas four patients entered the immunotherapy group and one entered the control group at their own insistence. Immunotherapy improved the disease-free survival of patients in this trial. There was one recurrence with death in the 13 patients treated with preoperative intralymphatic MER-BCG; whereas four of seven patients in the control group had recurrence (P = 0.015), at all four of these patients died during the same interval.

Adjuvants, Immunologic↗
PubMed1981

Selectivity in the effects of indomethacin on BCG-activated suppressor cell populations.

Intravenous inoculation of BCG into C57 B1/6 mice activated natural suppressor cells in the bone marrow and induced suppressor cells in the spleen. The suppressor activity of these cell populations was determined by co-cultivating them with normal lymphocytes being immunized against allogeneic P815 cells in vitro. Six million cells from the spleen or bone marrow of BCG treated mice inhibited by more than 50% the alloimmunization of twenty million normal syngeneic lymphocytes. The suppressor cells were found in the nylon wool adherent population in spleen and in both the nylon wool adherent and non-adherent populations in bone marrow. Indomethacin, at a concentration of 10(-6)M, completely blocked the suppression generated by unfractionated spleen or adherent spleen from BCG treated mice. However, 10(-6)M and higher concentrations of indomethacin only partially blocked the suppression generated by unfractionated marrow or adherent marrow from BCG treated mice. The suppression generated by non-adherent marrow from BCG treated mice was completely insensitive to indomethacin.

Animals↗
PubMed1980

Structural evidence for distinct IgG subclass-specific Fc receptors on mouse peritoneal macrophages.

Membrane proteins which selectively bind to the Fc portion of IgG were identified in the Nonidet P-40 extracts of radiolabeled thioglycollate- elicited mouse peritoneal macrophages. Affinity columns of various IgG preparations coupled to Sepharose 4B were used to absorb the Fc-binding proteins. Analysis of the acetic acid or sodium dodecyl sulfate (SDS) eluates from aggregated human IgG or antigen-complexed rabbit IgG columns revealed two Fc(gamma)/-specific proteins with apparent 67,000 and 52,000 mol wt. These proteins were not detected in acid or SDS eluates from F(ab')(2) columns or in eluates from IgG column, over which were passed lysates of Fc receptor-negative cells. With the use of affinity columns that contained aggregated mouse myeloma proteins of different IgG subclasses, we found that the 67,000-dahon protein selectively binds to IgG2a, whereas the 52,000-dalton protein binds to IgG1 and IgG2b. Neither protein was found in SDS eluates from IgG3 columns. Trypsin treatment of the macrophages before detergent lysis removed the 67,000-dalton protein, although it leaves intact the 52,000-dalton protein. These results provide structural confirmation for the existence of separate Fc receptors on mouse macrophages and indicate that the two Fc-binding proteins identified in this study represent all or part of the trypsin- sensitive Fc receptor which binds IgG2a and the trypsin-resistant Fc receptor which binds IgG2b and IgG1.

Animals↗