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Biomedical subjects

R C Burton

Publications and source records attributed to R C Burton.

At least 73 records · Page 4Linked to original sources
PubMed1983

Effects of age, gender, and cigarette smoking on human immunoregulatory T-cell subsets: establishment of normal ranges and comparison with patients with colorectal cancer and multiple sclerosis.

Normal ranges for peripheral circulating mature functional T cells (OKT3+), T helper-inducer cells (OKT4+), and T cytotoxic-suppressor cells (OKT8+) were determined in 161 normal male and female volunteers. Children between 5 and 15 years of age showed higher circulating OKT3+ cell numbers than adults, and in male children the circulating OKT4+ cell number was also higher. In adults, females demonstrated higher circulating OKT4+ cell numbers than males, and smokers demonstrated higher circulating numbers of both OKT3+ and OKT4+ cells than nonsmokers. There was a significant interaction between gender and smoking, with female smokers exhibiting the highest circulating OKT3+ cell numbers. Two groups of patients entering longitudinal T-cell subset monitoring studies were compared to their appropriate normal control groups. It was found that 48% of patients with colorectal cancer were T-cell (OKT3+) lymphopenic at presentation, and that 62% had a low OKT4/OKT8 ratio. Colorectal surgery tended to correct this T-cell lymphopenia. However, only transient rises in low OKT4/OKT8 ratios were observed after surgery. Of 11 patients with multiple sclerosis in a trial of transfer factor therapy, 7 were found to have high OKT4/OKT8 ratios prior to treatment; these ratios have persisted to date during treatment.

Adolescent↗
PubMed1983

Studies of allogeneic tumor transplants: induced rejection of advanced tumors by immune alteration of recipients.

In the present experiments, a methylcholanthrene-induced sarcoma (S-702) of B10.D2 origin was found to grow rapidly in B6AF1 mice leading to the death of all recipients in 5 to 9 wk. Nevertheless, immunity to MHC antigens presented by the tumor was readily demonstrable in tumor-bearing mice by their responses to donor strain skin grafts until late in the course of tumor growth, when a nonspecific form of immune suppression developed. In addition, B6AF1 mice preimmunized by exposure to B10.D2 donor strain antigens did not permit tumor growth. Treatment of tumor-bearing B6AF1 mice with CY at 18 days, when the tumors measured over 12-mm in diameter, followed by the i.p. injection of B10.D2 lymphoid cells (at a dosage of from 1.2 to 2.5 X 10(8) cells) resulted in the complete regression of 100% of these large tumors. CY treatment combined with localized immune stimuli in the form of donor strain skin grafts or secondary tumor implants was incapable of producing a sufficiently heightened immune response to cause tumor rejection. A dose of CY temporarily retarded tumor growth in most mice, and in a minority of animals so treated (less than 25%) tumors regressed completely. In syngeneic (B10.D2) animals, CY also temporarily slowed tumor growth, but total regression was never observed. An effective B10.D2 cell inoculum could consist not only of living lymphoid cells but of irradiated (1000 rad) cells as well. Tumor cell suspensions (after irradiation, 10,000 rad) were also effective. These observations suggest local immune factors at the host-tumor interface may have been of importance in the survival of these allogeneic tumor transplants and that CY influenced this state, perhaps through an influence on suppressor cells, allowing subsequent administration of donor strain cellular antigens to induce an effective tumor rejection response.

Animals↗
PubMed1983

The presence of NK alloantigens on cloned cytotoxic T lymphocytes.

A panel of sera raised against NK-1.1 and NK-2.1 alloantigens was tested for reactivity against a panel of cloned antigen-dependent CTL lines. By using indirect immunofluorescence and flow cytofluorimetry, weak, but clear and consistent, reactivity was found on all CTL. Concordant with the genetics of NK alloantigens, C57BL/6-derived clones were reactive with anti-NK-1.1 and anti-NK-2.1 sera, whereas CBA-derived clones were reactive with anti-NK-2.1 sera but not with anti-NK-1.1 sera. Cloned CTL lines were also able to partially and specifically absorb the antibodies from NK alloantiserum that reacted with splenic NK cells. These results indicate that cloned CTL lines express at least some of the NK alloantigen determinants present on splenic NK cells and have important implications regarding the relationship of CTL and NK cells.

Animals↗
PubMed1982

Mechanisms of syngeneic tumor rejection. Susceptibility of host-selected progressor variants to various immunological effector cells.

The ultraviolet radiation-induced fibrosarcoma 1591 generally is rejected by normal syngeneic mice and only rarely exhibits progressive growth. We isolated five of these rare progressor tumors from normal animals to determine the selective pressures that had been exerted upon the parental tumor by normal immunocompetent hosts. We found that the variant tumor cell lines could neither induce nor be killed by tumor-specific lymphocytes, suggesting that selection had been exerted against tumor cells expressing the tumor-specific antigen. In contrast, no selection against natural killer cell activity or against nonspecific T cell-mediated immunity seems to have occurred because progressor tumor cells were highly sensitive to these types of effector cells and in fact induced these effector cells more effectively than did the parental tumor. Nude mice were found to be as capable as normal mice in generating natural killer activity in response to a challenge with progressor tumor cells, but they were unable to mount a nonspecific T lymphocyte response. This may account for the fact that the progressor tumors grew at a significantly faster rate in nude animals than in normal mice. Thus, our study shows that in this tumor system nonspecific T cell-mediated immunity may play a role in retarding tumor growth, but the absolute resistance of normal animals to progressive tumor growth critically depends upon the presence of T cell-mediated tumor-specific immunity. Furthermore, neither NK cells nor nonspecific cytotoxic T lymphocytes appear to play a role in immunoselection against this tumor in normal immunocompetent hosts.

Animals↗
PubMed1982

Tumor immunity to murine plasma cell tumors. VII. Expression of H-2 and tumor antigens on Ig synthesis variants of MPC-11.

As a part of our continuing investigations directed toward defining the nature of the antigens on murine plasmacytomas (PCT), MPC-11 and two immunoglobulin (Ig) synthesis variants of this cell line were examined for H-2 and tumor-associated antigen (TAA) expression, and for the possible role of H-2 in the cytotoxic T lymphocyte response to TAA. The tumor lines studied were MPC-11 (an IgG2b producer), MPC-11,662 (a variant which produces only light chains), and NP.2 (a variant which produces neither Ig chain). Both H-2 expression, which was analyzed by flow cytometry and by cold target cell blocking of the activity of cytotoxic T lymphocytes (CTL) generated in allogeneic cultures, and TAA expression, which was analyzed by cold target cell blocking of the activity of tumor-specific CTL generated in syngeneic cultures, were found to be quantitatively similar on the three lines. When a possible association between H-2 and TAA expression was examined by testing the ability of anti H-2 sera to block tumor-specific CTL directed against MPC-11, no association between H-2 and TAA was detected. The results of these studies provide new information about H-2 and TAA expression on murine PCT. Furthermore, they suggest that changes in H-2 and TAA expression which have been reported to sometimes accompany loss of Ig synthesis may represent independent genetic, phenotypic, or metabolic variations, rather than alterations linked to the loss of Ig synthesis. In addition, these results, in agreement with out previous studies on MPC-11, support the concept that there is not an obligatory association of TAA with H-2 on the surface of murine PCT. Because these results differ from those reported in some other systems in which an association between H-2 and TAA on murine PCT was demonstrated, it must be emphasized that the TAA of PCT appear to be quite heterogeneous, and more investigations will be necessary in order to clearly define these antigen and the T-cell response to each of them.

Animals↗
PubMed1982

Studies on natural killer (NK) cells. Heterogeneity of NK cells in beige mutant mice.

Mice homozygous for the recessive beige mutation show grossly impaired natural killer (NK) activity against lymphoma targets in short term assays. When spleen cells from homozygous C57 BL/6 and B6C3F1 beige mutant mice were examined in assays of up to 30 h duration and tested with anti-NK-1 . 2 antiserum prior to assay, it was found (1) that the impaired NK-1 . 2+ (NKA) activity against lymphoma targets could be partially or wholly overcome by prolonging the assay time to greater than 12 h, (2) the NKA activity as revealed by prolonged assay times showed considerable variability in homozygous beige mutant mice (from greater than or equal to 4-fold less than to 2-fold greater than that of normal controls), (3) that NK-1 . 2- (NKB) activity against two non-lymphoma targets was normal in these mutant mice and (4) that two independently derived beige mutations had the same effects on NKA and NKB cell activity.

Animals↗
PubMed1982

An NK-like cell limits the adoptive response from "pre-progenitor" B cells.

Evidence is presented that a dividing, Thy 1 . 2 positive and NK 1 . 2 positive cell with a suppressive effect on adoptive responses is present in the spleens of normal and athymic mice, and that its function may be enhanced by non-specific antigenic stimulation. NK cells may thus exert a controlling function on the proliferation and differentiation of B cells. The main experimental observation is that under certain assay conditions incubation of spleen cells with 3H-TdR in order to kill dividing, non-specifically activated 'pre-progenitor' B cells may actually give a marked increase rather than a decrease in a subsequent hapten-specific primary adoptive response. An activated 'suppressor' population was proposed as the reason for this effect. This anomalous effect may be avoided and the cycle state of the B cells assessed by prior elimination of cells bearing Thy 1 antigen, together with the use of a more reliable hydroxyurea incubation to kill dividing B cells.

Animals↗
PubMed1982

T-lymphocyte subsets in smoking and lung cancer: Analysis of monoclonal antibodies and flow cytometry.

In order to determine whether abnormalities of immunoregulatory T-cells occur in patients with lung cancer, we characterized peripheral T-lymphocytes in 26 patients with untreated lung cancer. The results in patients with primary squamous cancer (SC) (n = 10), primary adenocarcinoma (AC) (n = 7), and secondary lung metastases (M) (n = 9) were compared with each other and to subjects without cancer (n = 48), including nonsmokers (n = 29) and smokers (n = 19). We found that OKT3+ (mature, peripheral (T-lymphocytes, including both OkT4+ (inducer/helper) and OKT8+ (cytotoxic/suppressor) lymphocytes, were increased in light-to-moderate smokers, but that OKT4+ cells were decreased n heavy smokers (p less than 0.05). The ratio of OKT4+ to OKT8+ (4/8) lymphocytes, reflecting the balance of immunoregulatory cells, was normal in light-to-moderate smokers, but was decreased in heavy smokers (p less than 0.05). The profile of circulating T-cells in patients with SC was similar to the smokers. In contrast, in patients with AC, we found a decreased percentage of OKT8+ cells (p less than 0.05). The 4/8 ratio was elevated in patients with AC (p less than 0.05). In patients with M, there was a decreased percentage of OKT3+ cells reflected in both OKT4+ and OKT8+ subsets. The 4/8 ratio in patients with M was low. Thus, a number of abnormalities in circulating T-cells was found both in smokers and in patients with lung cancer. These results suggest that immunoregulatory abnormalities contribute to the pathogenesis of lung cancer.

Adenocarcinoma↗
PubMed1982

Broadly reactive murine cytotoxic cells induced in vitro under syngeneic conditions.

Mouse spleen cells became cytotoxic in short-term 51Cr-release assays for a wide variety of target cells after 5 days of culture in vitro with polyinosinic acid in a system that was otherwise entirely syngeneic. This study characterizes these effector cells with respect to target specificity, effect of donor age, time course of their appearance, mouse strain differences, and expression of differentiation antigens Thy-1, Lyt-1, Lyt-2, NK-1, and asialo GM1. The combination of properties of this cytotoxic cell response that make it unique are that a) the broadly reactive cytotoxic activity developed from unprimed spleen cells in the absence of either foreign cells or foreign serum; b) the response did not peak until 4 to 5 days of culture in vitro; c) the broad reactivity pattern included freshly dispersed primary syngeneic sarcoma cells and cultured syngeneic fibroblasts but did not include syngeneic lymphoblast target cells; d) the response was largely monoclonal as defined by target cell binding; and e) cytotoxic cell activity was sensitive in complement-mediated treatments to both anti-NK and anti-theta but not to anti-Lyt-2, anti-Lyt-1, or anti-asialo GM1. Both high- and low-responding mouse strains have been identified.

Animals↗
PubMed1982

Monoclonal antibodies to human T cell subsets: use for immunological monitoring and immunosuppression in renal transplantation.

Sequential monitoring of peripheral blood T cell populations was performed in normal control individuals and in 55 renal allograft recipients. In addition, 66 patients exhibiting prolonged renal allograft survival were each evaluated at least once with the same monoclonal antibodies. A normal or elevated OKT4:OKT8 ratio, especially in the presence of rising numbers of OKT4+ cells was predictive of possible future graft rejection. This observation, when followed by rising serum creatinine values coupled with biopsy evidence of glomerulopathy, was found in at least 15% of graft recipients. In a small number of patients, graft rejection episodes were successfully suppressed by administration of therapeutic doses of OKT3 antibody. However, production of anti-OKT3 antibodies was observed and may be expected to limit administration of this agent to a single short course in each patient.

Acute Disease↗
PubMed1982

T cell responses to alloantigens. IV. In vivo and in vitro studies of the abrogation of presensitization to major histocompatibility antigens.

B6AF1 mice were sensitized to major histocompatibility complex (MHC) antigens by rejection of B10.D2 skin allografts. The effects of various protocols of treatment with antithymocyte serum (ATS), Bordetella pertussis vaccine, and donor strain lymphocytes were tested in these mice, and the results were assessed by in vitro testing for abrogation of circulating cytotoxic T cell memory and in vivo by determining the survival time of a second donor strain skin graft. It was found that a 6-week course of ATS alone abrogated this presensitized state as judged by both the in vitro and in vivo measurements, and that the hyporesponsive state induced by this treatment persisted for at least 4 months.

Animals↗
PubMed1982

Studies on natural killer (NK) cells. III. The effects of in vitro culture on spontaneous cytotoxicity of murine spleen cells.

In vitro culture of normal lymphohemopoietic cells is a complex event leading to the generation of a diverse group of effector cells. When murine spleen cells are cultured by themselves in fetal calf serum containing medium for up to 9 days, at least 3 distinct subpopulations of cytotoxic effectors can be distinguished on the basis of tumor target cell preference and expression of cell surface alloantigens. Fresh spleen cell suspensions contain 2 distinct NK cell types: NK-1.2+ NKA cells, which preferentially lyse lymphoma targets, and NK-1.2- NKB cells, which lyse nonlymphoma, mainly solid tumor targets. These NK cells account for all the cytolytic activity on day 0 of culture. NK-1.2+ NKA cells are very labile, and greater than or equal to 80% of their activity is lost within 48 hr of culture. By contrast, the activity of NKB cells increases in culture, up to 4-fold by day 6, and solid tumor target cells resistant to lysis by fresh spleen cells now become susceptible. In addition, an NK-1.2-, H-2+, Thy-1.2+, Ly-1.2+, Ly-2.2+ cytotoxic effector cell arises in culture from, or is dependent upon the presence of, NK-1.2-, Thy-1.2+ cells. This spontaneously arising "Tc" has a peak of activity between day 3 and 6 of culture, and kills a variety of lymphohemopoietic tumor cell types.

Animals↗
PubMed1981

Use of monoclonal antibodies to T-cell subsets for immunologic monitoring and treatment in recipients of renal allografts.

Using monoclonal antibodies and flow cytometry, wer serially monitored lymphocyte subpopulations in renal-allograft recipients treated with either conventional immunosuppression or a monoclonal antibody. In 29 patients given conventional suppression, highly significant correlations between changes in T-cell subsets and rejection were noted. Normal or elevated ratios of OKT4 (helper/inducer) to OKT8 (suppressor/cytotoxic) cells were associated with rejection unless the donor was HLA identical or the total number of T cells was extremely low. In patients with low ratios, rejection seldom occurred. Two patients treated with OKT3 monoclonal antibody for acute rejection had rapid disappearance of OKT3-reactive cells from the peripheral blood and prompt reversal of rejection. The use of monoclonal antibodies allows the precise determination of changes in T-cell subsets and promises the development of therapeutic protocols that can be designed to manipulate selected lymphocyte populations.

Antibodies↗
PubMed1981

Heterogeneity of natural killer cells in the mouse.

Mice were treated with the bone-seeking isotope, 89Sr, cyclophosphamide, and short-term lethal irradiation in vivo, and murine spleen cells are treated with anti-Nk-1.2 plus complement (C) in vitro. Fresh spleen cell suspensions from the above groups and from beige and neonatal mice were subsequently tested for natural killer (NK) cell activity against a panel of lymphoid and nonlymphoid tumor cell target. NK cell reactivities against YAC-1, MPC-11, and Cl.18 tumors were markedly and consistently reduced in (a) mice treated with 89Sr, (b) spleen cells treated with anti-Nk-1.2 plus C, and (c) C57BL/6 bg/bg mice. In contrast, NK activities against FLD-3 and WEHI-164.1 tumors were usually normal in mice treated with 89Sr, in beige mutant mice, and in spleen cells after treatment with anti-Nk-1.2 antibody and C. It appears, therefore, that two major groups of NK cells exist in fresh mouse spleen cells suspensions. NK-A cells are marrow dependent, Nk antigen positive, and deficient in beige mice; these lyse YAC-1, MPC-11, and Cl.18 tumors. NK-B cells, which are responsible for the lysis of WEHI-164.1 and FLD-3, are Nk antigen negative, marrow independent, and unaffected by the bg/bg mutation. Other features of NK-B cells, suggest that these NK cells, although they share the characteristics mentioned above, differ among themselves especially with respect to age of maturation and susceptibility to cyclophosphamide and total body irradiation. The NK-B group may therefore induce subsets that remain to be defined.

Aging↗
PubMed1981

The effect of infection on T lymphocyte subpopulations: a preliminary report.

The effect of cytomegalovirus (CMV) infection on T-lymphocyte subpopulations (employing the monoclonal antibody OKT4 to delineate helper cells and OKT8 for suppressor-cytotoxic cells) was studied in 10 normal individuals with CMV mononucleosis and four renal transplant patients with symptomatic primary CMV disease. In both clinical settings, acute CMV infection is associated with a reversal of the normal helper/suppressor-cytotoxic T cell ratio, with both a relative and absolute decrease in T helper cells and an increase in T suppressor-cytotoxic cells observed. With clinical recovery, there is a return of these cell populations toward normal ranges. In two patients, one with chronic CMV infection and one with chronic Epstein-Barr virus infection, the helper/suppressor-cytotoxic cell ratio was found to be reduced four years after the onset of infection. Five patients with febrile illnesses were also studied: two with viral infection and one with a self-limited febrile illness had decreased helper/suppressor-cytotoxic cell ratios, and two with bacterial infection had increased ratios. Thus, delineation of T lymphocyte subpopulations may be of value not only in evaluating the immunologic effects of a particular infectious agent, but also in the clinical evaluation of the febrile patient.

Animals↗