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Biomedical subjects

R M Gorczynski

Publications and source records attributed to R M Gorczynski.

At least 163 records · Page 9Linked to original sources
PubMed1980

Individual-specific (idiotypic) T-B cell interactions regulating the production of anti-2,4,6-trinitrophenyl antibody. II. Development of idiotype-specific helper and suppressor T cells within mice making an immune response.

The previous report demonstrated that serum and cells from CBA mice immunized with trinitrophenyl (TNP), when injected into normal, syngeneic "recipient" mice, induce the formation of apparently idiotype-specific suppressor cells and serum factors, and that such regulatory elements develop within the serum of the TNP-immunized animals themselves. In this report, it is indicated that regulator cells develop also within the spleens of TNP-keyhole limpet hemocyanin-immunized animals, and may in part be responsible for our earlier observation that T cells from TNP-immune CBA mice stimulate optimal antibody production in culture when paired with B cells from the same individual animal. While some evidence for individual-specific T helper cells was obtained, the poorer response of mismatched T and B cells could be attributed in part to Ly-2.2-bearing suppressor T cells. Overall, the results support the view that idiotype-related regulation is not confined to dominant-idiotype models but is also involved in heterogeneous anti-hapten antibody responses.

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PubMed1980

In vitro generation from murine brow marrow cells of accessory cells with discrete antigen presentation capacity and ability to release lymphostimulatory molecules.

An investigation of the immunological accessory cell function of in vitro bone marrow derived colony forming cells has been made. Data are presented to show that such cells can present immunogenic stimuli to lymphocytes and release lymphostimulatory products that in turn replace certain macrophage functions in the immune response. The appearance of these two activities is not correlated. Considerable heterogeneity exists in terms of the ability of different populations of cells to present distinct carbohydrate antigens in immunogenic form. In addition, that different macrophage cell populations can alter the affinity of antibody produced by an optimally stimulated primed spleen cell population is reported.

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PubMed1980

Inheritance of acquired immunological tolerance to foreign histocompatibility antigens in mice.

CBA mice were rendered tolerant of major histocompatibility antigens of A/J mice by neonatal injection of 100 x 10(6) lymphoid cells of (CBA X A/J)F1 followed by repeated injections of F1 cells at 2-week intervals throughout the study. When adult (8 weeks old), 10 tolerant or normal CBA males were mated to normal CBA females. Spleen cells of the progeny were tested for their ability to mount a cytotoxic T lymphocyte response in vitro against A/J antigens or against C57BL/6J and B10.A (2R) antigens in a cell-mediated lympholysis (CML) assay. A significant proportion (50-60%) of first-generation offspring of tolerant fathers failed to produce detectable anti-A/J cytotoxic responses but responded in the normal range to stimulation by C57BL/6J or B10.A (2R). Second-generation offspring derived from mating animals born of tolerant male parents--either brother x sister matings (incross or matings to normal CBA mice (outcross)--also showed a high proportion (20-40%) with diminished anti-A/J CML responses when similarly tested in vitro. Thus, a specific acquired somatic characteristic in the immune system (tolerance to major histocompatibility antigens) induced in male mice shows significant transmission to first- and second-generation offspring.

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PubMed1980

Restriction of antigen recognition in mouse B lymphocytes by genes mapping within the major histocompatibility complex.

B cells, like T cells, show genetic restrictions in their interactions with other cells. B cells from (C3H/HeJ X C57BL/6J)F1 mice were stimulated with foreign antigen (sheep erythrocytes, SRBC) in parental-strain irradiated hosts. They could be subsequently activated to antibody formation in vitro by SRBC presented on cells of the same parental type, and much less by SRBC on cells of the other parental type. The restriction was seen whether antigen was presented on macrophages or by activated T cells. Experiments with congenic mice showed that the restriction was controlled by the MHC locus. Restriction of F1 B cells to responsiveness against either parental haplotype was much more readily induced in bone marrow than in splenic populations. This restriction could be broken down by giving the irradiated host a second injection of antigen 3 weeks after the first; this probably reflects "reeducation" of the F1 B cells by SRBC associated with donor, F1-type macrophages. Normal unprimed spleen B cells also showed a strong preference for activation by SRBC in association with syngeneic activated T cells.

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PubMed1979

A novel biological function of macrophages associated with antigen discrimination properties.

The ability of fresh or cultured subpopulation of adherent peritoneal exudate cells to perform discrete biological functions commonly associated with macrophages, namely antibody dependent cytotoxicity (ADCC) and phagocytosis, has been compared with the ability of the same cells to present TNP coupled to carbohydrate or protein carriers for a subsequent antibody response, or semi-allogeneic cells for T cell cytotoxic responses, in tissue culture. Data are presented to show that ADCC reactivity rapidly disappears on cultures of peritoneal cells, though phagocytic activity is more persistent throughout the 14 days of culture. When ADCC activity reappeared it was no longer restricted to those fractions active initially. Antigen handling of different TNP-protein conjugates was pronounced throughout the culture period and was not easily explained in terms of the ADCC/phagocytic activity of the macrophage subpopulation concerned. In contrast, however, antigen handling of carbohydrate antigens for presentation to T or B lymphocytes by the different macrophage populations varied during the culture period in fashions which were in some degree correlated with the phagocytic activity of the various cells but were also a function of the antigen under consideration. These data are interpreted in terms of a novel role for the macrophage in discrimination of carbohydrate antigens for presentation to lymphocytes.

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PubMed1979

The role of macrophages in stimulation of immune induction and myelopoiesis. I: Comparison of activity of macrophage-derived factors in granulopoiesis and immunostimulation.

Hemopoietic growth and immunological inductive factors from human peripheral leukocyte conditioned medium and mouse macrophage culture supernatant fluids were compared. Factors derived from human peripheral leukocyte conditioned medium were found to substitute for those of mouse macrophage derivation in immunological assays, namely, induction of a cytotoxic T-lymphocyte response in macrophage-depleted mouse spleen cultures. Association of macrophage-derived factors with B2-microglobulin (B2m) antigen determinants was observed by inhibition with great antihuman B2m, affinity chromatography, and direct replacement of mouse macrophage-derived factors with human urinary B2m.

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PubMed1979

The role of macrophages in stimulation of immune induction and myelopoiesis: II: analysis of genetic restriction involved in the stimulation of granulocyte colony precursors or mature lymphocytes using factors prepared from different recombinant inbred strains of mice.

The genetic restriction involved in the reconstitution of immune responses in macrophage-depleted mouse spleen cultures, or the induction of colony formation in bone marrow cultures, by different molecular-weight species of lymphostimulatory molecules derived from mouse peritoneal cell suspensions is reported. The data suggest little evidence for genetic restriction in the ability of any of the factors to stimulate bone marrow colony formation in vitro. However, when immunological stimulation was investigated, a restriction coded for by genes in the K/D end of the MHC (70-90K factor) or in the I region of the MHC (30-45K factor) was observed. A third species of lymphostimulatory molecule (15K) showed no such restriction. Further evidence is presented to suggest that the active moiety in the 70-90K molecule(s) is a 15K-like species (nonrestricted in its ability to reconstitute cells from different strains of mice.

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PubMed1979

Effect of gold sodium thiomalate on murine lymphocyte functions.

The in vitro effects of gold sodium thiomalate (GTM) on various murine splenic lymphocytic functions were tested. The presence of GTM in cultures of splenic cells suppressed anti-hapten responses to both thymus-independent and thymus-dependent antigens. GTM also suppressed the in vitro generation of cytotoxic effector cells as well as the mitogenic response to both T cell and B cell mitogens. This suppression could not be reversed by the addition of irradiated spleen cells. Spleen cells exposed to GTM for 4 hr prior to culture also exhibited similarly suppressed functions, although their functional capacity could be fully restored by the addition of irradiated spleen cells. These results show that GTM inhibits both humoral and cellular immune mechanisms and appears to act primarily at the accessory (macrophage) cell level, with perhaps a secondary effect on T lymphocytes.

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PubMed1979

Suppression of cytotoxic response to histoincompatible cells. I. Evidence for two types of T lymphocyte-derived suppressors acting at different stages in the induction of a cytotoxic response.

Spleen and thymus cell populations from normal or allograft tolerant mice have been cultured for 5 days with specific alloantigens and examined for their reactivity in three assay systems. No consistent correlation was observed between the production of cytotoxic T cells (CTL) in these cultures and the ability of such cultured cells to inhibit specifically a CML response from fresh normal spleen cells directed to the priming alloantigens. Furthermore, suppressor cells measured in this latter assay were apparently distinct from those able to inhibit the production of cytotoxic lymphocyte precursors (CTLp) from bone marrow stem cells in lethally irradiated bone marrow protected mice. Velocity sedimentation experiments confirmed that both the precursor and effector cells for the two suppressor systems were physically separable, and were distinct from CTLp or CTL, respectively. Precursor cells for the two suppressor systems investigated belong to the short-lived cortical thymus cell population.

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PubMed1979

Suppression of cytotoxic response to histoincompatible cells. II. Analysis of the role of two independent T suppressor pools in maintenance of neonatally induced allograft tolerance in mice.

The kinetics of appearance of the precursors of SuppA cells (capable of inhibiting CTLp leads to CTL) or SuppB cells (capable of inhibiting (stem cells leads to CTLp) in neonatal mice, as well as the appearance of SuppA/SuppB cells in mice given neonatal innoculations of semiallogeneic spleen cells has been investigated. The data obtained are consistent with the idea that SuppA cells have a natural role to play in the induction of neonatal tolerance, whereas SuppB cells may be more important for the maintenance of the tolerant state. Unlike the level of SuppB cells, the level of SuppA cells in tolerant mice seems to be modulated by the presence of the tolerizing determinants. Data are provided to show that SuppB cells, once induced in tolerant mice, can adoptively transfer specific allograft unresponsiveness to newborn syngeneic mice in the absence of added tolerizing antigen, whereas SuppA cells are not able to do so. These data fit the notion that SuppB cells may be responsible for the phenotype of clonal deletion.

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PubMed1979

Differentiation of functionally active mouse T lymphocytes from functionally inactive bone marrow precursors. III. Induction of T-cell activities by growth of bone marrow on feeder layers prepared from mouse thymocytes.

The ability of small and large T precursor cell pools to differentiate into mature functional T lymphocytes on thymus feeder cell layers or in the presence of a supernatant prepared from such feeder layers was compared. Evidence was obtained showing that the small cell pool differentiated as effectively in the presence of soluble factors prepared from the thymus cultures as in the presence of the thymus cells themselves. In contrast, large stem cells apparently needed cellular contact with the thymus feeder cultures in order to promote differentiation, though a time point could be found at which further differentiation from this precursor pool would also occur in the presence of the thymus culture supernatant only. These data concurred with evidence from in vivo experiments for two pools of T-cell precursors which differentiated in thymectomized or thymus-intact recipients respectively.

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PubMed1979

Differentiation of functionally active mouse T lymphocytes from functionally inactive bone marrow precursors. IV. Recovery of T-cell function from bone marrow precursors in a histo-incompatible environment.

Regeneration of T-cell activities in vivo or in vitro from mouse bone marrow precursors differentiating in the presence of an allogeneic thymus was investigated. The data indicated that T-depleted bone marrow cells fail to affect long-term reconstitution of allogeneic recipients unless a pool of rapidly maturing T-precursor cells is also removed (post-thymic pool). Animals reconstituted with pre-thymic bone marrow stem cells become stable chimaeras in which cells capable of generating an in vitro CML response to host antigens, as well as cells capable of suppressing that response, could be demonstrated. Similar data (CML directed against the H-2 antigens of the 'host' thymus feeder layer and cells capable of inhibiting that response) were obtained when pre-thymic bone marrow cells were grown in vitro on allogeneic thymus feeder cells. When cytotoxic T-lymphocyte precursor (CTLp) and helper (CTLh) cells were separately investigated, a restriction in their co-operation for an anti-host response was observed when precursor cells differentiated in an allogeneic environment. Only CTLp and CTLh differentiating in the presence of the same allogeneic thymus source (whether in vivo or in vitro) could co-operate to generate CTL directed to H-2 antigens of that thymus source.

Animals↗
PubMed1979

MHC restriction of murine T lymphocyte reactivity analysed by growth of bone marrow cells in vitro on thymus epithelial monolayers.

Mature mouse T lymphocytes, derived from long-term culture of bone marrow cells on thymus epithelial monolayers, were analysed with respect to their ability to co-operate with B cells (for antibody production) or T cells (in the generation of cytotoxic cells) when the bone marrow T precursor cells and the thymus epithelial cells differ at defined regions of the major histocompatibility complex. A pool of more mature bone marrow T-cell precursors gave rise to T cells interacting only with T/B lymphocytes sharing MHC determinants with the strain of origin of the bone marrow cells used. In contrast, a more immature bone marrow T-cell precursor pool produced T lymphocytes which had acquired MHC restriction (in terms of co-operativity with T/B cells) as defined by the MHC determinants of the thymus epithelium, and not those MHC determinants of the cultured bone marrow population. In addition, some evidence was obtained for Ir gene control (mapping in the MHC region) in the development of the repertoire of T cells involved in production of cytotoxic responses in vitro to TNP-modified self antigens.

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PubMed1978

Requirement for matching T cell and B cell subsets in secondary anti-hapten antibody responses.

The in vitro secondary anti-hapten response to trinitrophenylated keyhole limpet hemocyanin (TNP-KLH) has been investigated using B and T cells from the same or a pool of identically primed syngeneic individuals. The optimum antibody response obtained from B cells of any given animal was seen when the same individual's T cells were used as a helper cell source. This individual preference was lost if secondary challenge in culture was made with TNP on a heterologous carrier, with the helper cells obtained from suitably primed individuals or a pool thereof. These data are interpreted in terms of a network theory for the regulation of immune responses under physiological conditions.

Animals↗
PubMed1978

Response of tumour-related and normal lymphocytes to antigens on fibroblasts from embryos of varying age.

The in vitro cytotoxic immune response of spleen lymphocytes from primiparous and tumour-related mice to embryonic cells from embryos of varying age and tumour cells has been investigated. The results indicate that lymphocytes from both primiparous and tumour-related (i.e., tumour-bearing or tumour-excised) animals give a response which is greater than that from cells from control mice ("virgin cells"). Moreover, in this putative anamnestic response the immune cells detect antigenic differences in the cell populations of embryos of varying age, which are not as readily demonstrable when cytotoxicity is derived from virgin cells. As a further indication of the in vivo priming to embryo-assoicated antigens, the data show that the precursors of cytotoxic cells apparently undergo a blastogenic response in the presence of embryo antigen, and revert to small quiescent cells when antigen is removed, in a way entirely analogous to that described for reactivity of mixed leucocyte cultures to antigens of the major histocompatibility complex. Finally, it seems that in animals immediately after removal of embryonic antigen (and to a lesser degree in virgin or late-embryo-immune mice) there exists a suppressor cell population which inhibits an anti-embryo cytotoxic response far more than an antiallograft response.

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PubMed1977

Role of macrophage-derived factors in generation of cytotoxic and antibody responses.

The ability of macrophage subpopulations, separated by virtue of differences in size, to liberate soluble factors able to reconstitute antibody and cell-mediated immune responses in macrophage-depleted lymphoid cultures has been investigated. Evidence is presented to show that all macrophages release trypsin- and pepsin-sensitive molecules with molecular weights of 30,000 to 35,000 and 50,000 to 70,000 that are able to reconstitute only syngeneic lymphocyte responses. In contrast, a molecule(s) with molecular weight of 10,000 to 15,000 daltons is released only by large macrophages and can apparently reconstitute both syngeneic and allogeneic lymphocyte responses. This material is also pepsin-sensitive and, to a lesser degree, trypsin-sensitive.

Animals↗
PubMed1977

Differentiation of functionally active mouse T-lymphocytes from functionally inactive bone marrow precursors.

An investigation has been made of the development of various T cell functions in lethally irradiated mice reconstituted with anti-0 treated spleen or bone marrow cells. Evidence is presented to show that both organs contain a post-thymic precursor pool able to regenerate by 15 days limited T cell responses in thymectomized recipients. A prethymic pool also exists in each organ able to regenerate, at a later date, first a suppressor T cell population and probably later, mature functional T cells involved in helper functions and cell mediated lympholysis. The spleen is apparently a better source of precursors of the suppressor cells than bone marrow, while a poorer source of precursors of the other T cell functions. All T cell functions investigated apparently first appear in large cells which undergo a reversion to small cells without necessarily maturing to their full potential reactivity. By following the kinetics of appearance of T cell functions, and the physical parameters of the cells with which these functions are associated, it is shown that PHA responding and Con A responding cells, cytotoxic T cell progenitors, helper T cells for antibody production and helper T cells for cytotoxicity induction can all at some stage of differentiation be separated from one another.

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