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Biomedical subjects

G F Mitchell

Publications and source records attributed to G F Mitchell.

At least 253 records · Page 14Linked to original sources
PubMed1977

Studies on antigen-induced arthritis in mice. II. Immunologic correlates of arthritis susceptibility in mice.

Antigen-induced arthritis was developed in mice as a model of human rheumatoid arthritis by using methylated bovine serum albumin (mBSA) as antigen. It was found that most strains were susceptible, whereas CBA mice were resistant. We therefore investigated the humoral and cell-mediated immune responses to mBSA in resistant mice (CBA) and susceptible mice (exemplified by C57BL) to determine whether these were associated with susceptibility to arthritis. The resistant strain (CBA) differed from the suceptible strains in the following respects. First, there was a lower humoral immune response to mBSA as measured by passive hemagglutination, but this could be overcome by a larger immunogenic dose. Secondly, there were differences in response to low doses of DNP-mBSA after mBSA carrier preimmunization. Thirdly, there were striking differences in delayed-type hypersensitivity (DTH) to mBSA as determined by a radioisotopic assay in vivo; the response of CBA mice occurred early, at 5 days, declined quickly, and was weaker, whereas that of C57BL mice developed later and was long sustained. Genetic studies of the DTH response with hybrids and backcrosses showed an oligogenic control of immune responsiveness, with one gene being linked to the H-2b allele of the susceptible C57BL mice, and another being independent of the H-2 complex. Our findings indicate that in mice, susceptibility to antigen-induced arthritis with mBSA correlates with a higher responder state to this antigen, and that T cells are the major if not the only determinant of the high responder state.

Animals↗
PubMed1977

Studies on antigen-induced arthritis in mice. III. Cell and serum transfer experiments.

Antigen-induced arthritis in mice occurs after immunization and subsequent intraarticular challenge with methylated bovine serum albumin (mBSA). In adoptive transfer experiments, susceptible C57BL mice and resistant CBA mice were compared in their capacity to express delayed-type hypersensitivity (DTH) by ear assay, and to express arthritis. The expression of DTH could be transferred incrementally by lymphoid cells in C57BL mice, but not in CBA mice. Both immune lymphoid cells and, to a much lesser extent, serum transferred the capacity to develop arthritis in C57BL mice. The reactivity of transferred cells was abolished by anti-Thy-1 but enhanced by enrichment for T cells with anti-immunoglobulin columns. If this model disease can be equated with human rheumatoid synovitis, the lesions in the human disease would be an expression of a T cell-dependent activity.

Animals↗
PubMed1976

Studies on immune responses to parasite antigens in mice. I. Ascaris suum larvae numbers and antiphosphorylcholine responses in infected mice of various strains and in hypothymic nu/nu mice.

In terms of day 7 lung larvae numbers, mice vary markedly in their suscepibility to a first infection with the nematode worms, Ascaris suum, and the highly susceptible strain, C57Bl, is resistant to second infection. Time course studies suggested that the period of residence in the liver or migration to, or into, the lungs are stages of the life cycle in which natural or acquired resistance of the host is expressed. The traits, susceptibility and resistance to first infection, were under polygenic control and no linkage of susceptibility to the major histocompatibility complex of C57Bl mice (H-2b) was observed. Acquired resistance (to second infection) has not been dissected because of our inability to show adoptive transfer of resistance to naive recipeints. Studies in hypothymic BALB/c. nu/nu mice indicate that natural resistance (to first infection) is not affected by a lack of T cells. The T cell dependence of acquired resistance in C57Bl mice remains in doubt although in the relatively resistant strain BALB/c, hypothymic nu/nu mice after second infection contain as many larvae in their lungs and liver as are present after first infection. An eosinophilia is observed in infected intact mice but not in infected T cell-deficient mice. Partially T cell-dependent serum antibodies and plaque-forming cells to phosphorylcholine (PC) were present in mice infected with A. suum but no evidence was obtained that this anti-PC antibody response was in any way protective for the host. The cell membrane-acitive properties of PC and related molecules suggest that PC-containing parasite antigens may be tolerogens for certain of the B cells with specificity for parasite antigens. A state of partial tolerance involving high affinity antibody production may be one means whereby parasites survive in natural or unnatural hosts.

Animals↗
PubMed1976

Studies on immune responses to parasite antigens in mice. II. Aspects of the T cell dependence of circulating reagin production to Ascaris suum antigens.

Heat-labile, rat skin-fixing antibodies were detected readily in the sera of young female mice dosed intranasally with the body fluid of Ascaris suum (ABF) and the adjuvant, Bordetella pertussis vaccine (BPV). In addition, washed cell suspensions prepared from spleen and the lymph nodes regional to the lungs were positive in an adoptive cutaneous anaphylaxis assay, an assay which may detect activities of reagins associated with mast cells rather than reaginic antibody-secreting cells. The intraperitoneal route was a poor means of inducing circulating anti-ABF reagins and an intraperitoneal injection of ABF + BPV delayed the appearance of circulating reagins in mice dosed at the same time with ABF + BPV intranasally. Hypothymic female BALB/c. nu/nu ('nude') mice failed to produce circulating reagins to ABF but an injection of normal thymocytes or cortisone-resistant thymocytes from syngeneic female mice led to higher titers of circulating reagins than found in normal female BALB/c. nu/+ littermates. Using cells from young male or female syngeneic donors and male and female BALB/c. nu/mu recpiients, evidence was obtained for a defect in the thymus of young male mice and conceivably this defect may extend to the peripheral T cell population in such mice. Cyclophosphamide pretreatment or adrenalectomy increased circulating reagin titers in normal mice dosed intranasally with ABF + BPV, and pretreatment with lipopolysaccharide intranasally markedly reduced titers of circulating anti-ABF reagins. In the discussion, emphasis is given to the hypothesis that potent allergens are T cell-stimulating, relatively persistent antigens which, when located in submucosal lymphoid sites and under conditions of limited antibody production as a result of limited recruitment of 'helper' T cells systemically, lead to the induction and sustained production of IgE by resident Bxi cells and their progeny.

Adrenalectomy↗
PubMed1976

Studies on immune responses to parasite antigens in mice. III. Nippostrongylus brasiliensis infections in hypothymic nu/nu mice.

Normal mice of several strains reject the nematode worm Nippostronglyus brasiliensis from the intestine within 14 days (and most often within 10 days) of injection of high numbers of infective third stage larvae (L3). Previously-infected mice are markedly resistant to a second infection. Hypothymic, nu/nu ('nude') mice continue to harbor worms long after intact mice have rejected the worm burden and an inoculum of T cells at the time of, or several days after L3 injection, leads to worm elimination within 14 days in nu/nu mice. As yet no evidence is available to indicate whether or not T cells with specificity for parasite antigens are required in a reconstitutive inoculum in nu/nu mice. Pretreatment of normal mice with cyclophosphamide, at doses reported to lead to temporary B cell hypofunction, does not result in delayed rejection of worms but the participation of B cell products (antibodies) cannot be discounted on the basis of this result. The nu/nu mouse - N. brasiliensis system will be useful in the search for, and characterization of, parasite antigens which gain access to the lymphoid organs and circulation of parasitized mice and in the analysis of T cell subtypes (both functional and surface Thy and Ly alloantigenic subtypes) involved in worm elimination.

Ancylostomatoidea↗
PubMed1976

Studies on immune responses to parasite antigens in mice. IV. Inhibition of an anti-DNP antibody response with the antigen, DNP-Ficoll containing phosphorylcholine.

Several nematode parasites contain phosphorylcholine (PC), and mice infected with Ascaris suum and Nippostrongylus brasiliensis produce IgM anti-PC antibodies. PC is a hapten which usually induces highly restricted antibody responses in mice and the conjugate DNP-Ficoll-PC inhibits an adoptive secondary anti DNP antibody response to DNP-flagellin whereas comparable doses of DNP-Ficoll and Ficoll-PC do not. The finding suggests that the restricted anti-PC responses to PC-containing antigens described in the literature may involve a degree of inhibition within the B-cell population (partial tolerance induction), that uni- and multi-cellular parasites of various types may 'utilize' molecules such as PC to induce a state of selective tolerance to parasite antigens, and that such a mechanism may be one means of facilitating survival of the parasites in their hosts and the production of antigenic variants of the parasite.

Animals↗
PubMed1975

Differences in the immunological activities of antibody-secreting cell precursors in mouse spleen selected on the basis of antigen-binding capacity.

Mouse spleen cells transfer a retarded and lower than normal IgG antibody response after removal of cells with a high antigen-binding capacity. The population enriched in these latter cells transfers a response equal to or, more often, higher than the response of the unfractionated controls and does not appear to have originated from previous priming of the mice. These cells are present in athymic nude mice and appear to be more susceptible to inactivation by an anti-Ig antiserum and complement than precursors of IgM antibody-secreting cells.

Animals↗
PubMed1975

T cell-dependent helper and suppressive influences in an adoptive IgG antibody response.

When immune spleen cells of mice immunized to a hapten carrier preparation 4 days previously were transferred to normal syngeneic hosts, they began to produce 7S antibody (presumably of the IgG class), provided that relatively small numbers of cells (about 1/10 spleen equivalent) were transferred. Increasing the number of transferred cells resulted in less IgG antibody formed. Depletion of the immune spleen cells of T cells by treatment with anti-theta serum and complement prevented IgG antibody formation. IgG antibody production by untreated and anti-therta serum-treated immune spleen cells could be enhanced (reinduced) by addition of small numbers of cells enriched for carrier-activated T cells. These suggest that T cells are necessary to stimulate antigen-activated B cells into IgG antibody production. Larger numbers of 'carrier-activated T cells' depressed IgG antibody production. Both enhancement and depression could be demonstrated to be antigen-specific. IgG antibody production high numbers of transferred immune spleen cells could be induced by treating the cells prior to transfer with suboptimal amounts of anti-theta serum and complement. It is argued that this results from the elimination of a T cell-dependent suppressor influence arising during a normal immune response.

Animals↗
PubMed1975

Promotion of secondary anti-DNP antibody production in mice by type III pneumococcal polysaccharide (SIII) and dinitrophenylated rabbit antibody to SIII.

Type III pneumococcal polysaccharide (SIII) is able markedly to increase the adoptive IgG ANTI-DNP antibody response of B cells primed to DNP-flagellin and stimulated with DNP conjugated to the heterologous carrier, rabbit globulin, provided the latter has anti-SIII activity. The stimulatory effect is apparently accessory cell-dependent as well as being unequivocally T cell-dependent. Although no positive evidence is available, the possibility exists that non-specific T-cell activation is involved in the stimulating effect of anti-SIII plus SIII.

Animals↗
PubMed1973

Histocompatibility-linked genetic control of disease susceptibility. Murine lymphocytic choriomeningitis virus infection.

Acute necrotizing inflammatory disease after intracerebral injection of LCM virus is largely dependent on the host immune response to the virus and is controlled, in part, by a dominant gene which is closely linked to the H-2 locus. The F(1) hybrid (H-2(q/k)) from mating a susceptible SWR/J mouse (H-2(q/q)) to a resistant C3H/HeJ mouse (H-2(k/k)) is susceptible to LCM virus disease. When such hybrids (H-2(q/k)) are backcrossed to susceptible parents (H-2(q/q)), all F(2) offspring (H-2(q/q), H-2(q/k)) are highly susceptible. In contrast, hybrid (H-2(q/k)) backcross to resistant parents (H-2(k/k)) results in half of the F(2) offspring being susceptible (H-2(q/k)) while the other half are resistant (H-2(k/k)). Similarly, in congenic H-2(q/q) and H-2(k/k) mice, H-2(q/q) mice are relatively susceptible to acute LCM disease, whereas H-2(k/k) are resistant.

Adsorption↗
PubMed1972

Immunological memory in mice. 3. Memory to heterologous erythrocytes in both T cell and B cell populations and requirement for T cells in expression of B cell memory. Evidence using immunoglobulin allotype and mouse alloantigen theta markers with congenic mice.

Using anti-allotype sera and AKR anti thetaC3H sera, a requirement for two cell types has been demonstrated in the adoptive secondary response of mice to heterologous erythrocytes. The cell types have been designated B cells [precursors of plaque-forming cells (PFC)] and T cells (thymus-influenced cells, not providing precursors of detectable PFC). The in vivo indirect PFC response of spleen cells from primed mice is markedly reduced by in vitro treatment of the cells with a mixture of anti-theta serum and guinea pig serum (Anti theta + GPS). This B cell response is fully restored to control levels by thymus cells from normal mice which do not themselves provide precursors of indirect PFC. Thus memory is carried by the B cell lineage but the expression of this memory is dependent on the presence of a cell population which is sensitive to Anti theta + GPS and which is replaced functionally by unprimed T cells. When assayed for T cell activity, thoracic duct cells from specifically primed mice are better than cells from nonspecifically primed mice in restoring the B cell response of spleen cells from immunized mice. Moreover, the T cell activity of a reconstitutive cell population from primed mice is reduced by incubation with Anti theta + GPS. We conclude that memory to heterologous erythrocyte antigens is carried by the T cell lineage as well as the B cell lineage even though unprimed T cells are sufficient for expression of B cell memory.

Animals↗