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R M Gorczynski

Publications and source records attributed to R M Gorczynski.

At least 19 recordsLinked to original sources
PubMed1992

The Drosophila per gene homologs are expressed in mammalian suprachiasmatic nucleus and heart as well as in molluscan eyes.

This study presents evidence for the conservation of Drosophila per gene homologs in mammalian DNA and for their expression in a number of tissues which are involved in various aspects of circadian timekeeping. Distinct 5 kb sequences, which hybridized to a non repetitive fragment of the Drosophila per gene under stringent conditions, were detected by Southern blotting. Sequences homologous to per gene of Drosophila were also amplified from rat and mouse brain cDNA libraries and from a mouse anterior hypothalamus and human hypothalamus libraries. Degenerate PCR primer design was based on conserved segments of the per protein. The per homologs were shown directly (by RT-PCR) to be expressed in hamster and mouse SCN, in hamster heart and in Aplysia and Bulla eyes.

Animals↗
PubMed1992

Immunosuppression induced by hepatic portal venous immunization spares reactivity in IL-4 producing T lymphocytes.

Immunization of naive or specifically primed C3H/HEJ with irradiated B10.BR spleen cells via the hepatic portal vein leads to an antigen specific decrease in the proliferative and cytotoxic response to B10.BR antigen assayed in vitro (and to increased graft survival of B10.BR grafts in vivo). This effect seems to be mediated in the main by a decrease in IL-2 production from CD4+ T lymphocytes of mice given antigen by the portal route, which is in turn caused by a decreased precursor frequency of IL-2-producing cells. No clear decrease in IL-4 production was seen. Hepatic APC isolated from mice receiving antigen via the portal vein were unable to induce IL-2 production from a C3H/HEJ anti-B10.BR cell line in vitro, in contrast to splenic APC derived from the same mice. Even when antigen was given by conventional (systemic) intravenous routes (in this case via the lateral tail vein) hepatic APC isolated from those mice were unable to stimulate IL-2 production from this cell line. Furthermore, 24 h exposure of a cell line to antigen pulsed hepatic APC left those cells refractory to a subsequent restimulation with antigen presented by splenic APC. Spleen lymphoid cells from primed mice challenged in vivo with B10.BR liver cells (i.v.) were similarly unable to produce IL-2 on rechallenge in vitro with irradiated B10.BR spleen cells, though no defect was seen if in vivo challenge was with B10.BR spleen cells. These data imply that presentation of multiple minor cell surface antigens by hepatic APC leads to specific anergization of IL-2 producing T cells, in a fashion which seems to be distinct from that previously reported as due to 'veto-like' activity.

Animals↗
PubMed1992

Antigen presentation by murine splenic, but not hepatic, antigen-presenting cells to induce IL-2/IL-4 production from immune T cells is regulated by interactions between LFA-1/ICAM-1.

Pretransplant transfusion of multiple minor histoincompatible spleen cells to naive recipient mice by the portal vein suppresses the ability of those animals to reject skin grafts from mice syngeneic with those used for transfusion, and decreases in vitro immunity on rechallenge with the same antigens, by comparison with mice receiving transfusion by the lateral tail vein. We have shown elsewhere that this is correlated with a diminished activation of Th1 cells for IL-2 production, without apparently affecting activation of Th2 cells for IL-4 production. Similar data are obtained by merely infusing hepatic (vs. splenic) antigen-presenting cells (APC) into normal mice, or by challenging immune cells in vitro with antigen-pulsed hepatic (vs. splenic) APC. However, when antigen-pulsed splenic APC are incubated with immune T cells in the presence of anti-LFA-1 monoclonal antibody (Mab), selective activation of Th2 cells (as is seen with hepatic APC) again occurs at the expense of activation of Th1 cells. Anti-LFA-1 Mab causes little perturbation in lymphokine production from T cells stimulated with hepatic APC. Using cDNA probes for IL-2 and IL-4 we show that T-cell activation in the presence of anti-LFA-1 Mab leads to selective inhibition of transcription of IL-2 mRNA.

Animals↗
PubMed1992

Conditioned stress responses by pregnant and/or lactating mice reduce immune responses of their offspring after weaning.

C3H/HEJ mice repeatedly exposed to rotational stress (45 rpm for 30 min) show a decreased immune response after challenge with sheep erythrocytes (SRBC) or multiple minor histoincompatible skin grafts (B10.BR) in association with the cues present when initially exposed to the physical stress. This conditioned immunosuppression is associated with diminished antibody production and enhanced skin graft survival. When previously conditioned mice were mated with normal (nonconditioned) males and reexposed to conditioning cues during pregnancy (days 13, 16, and 19 of gestation), the offspring of these mice were also found to produce a decreased antibody response (and decreased skin graft rejection response) when tested at 7 weeks of age. This altered immune response in the offspring occurred in the absence of any deliberate direct manipulation of these mice. In a further study a reciprocal crossover design was used to investigate whether altered immunity in the offspring was dependent upon the treatment of the biological mother and/or the fostering mother. The most marked immunosuppression was seen in offspring born to, and fostered on, conditioned mothers reexposed to cues previously associated with physical stress. However, even the offspring of of normal C3H/HEJ matings developed a reduced immune response if they were fostered on conditioned mothers reexposed to stress-associated cues. These data imply that the developing immune system is regulated by factors in the colostrum/feto-placental unit which are modified by conditioning phenomena.

Animals↗
PubMed1992

Comparison of functional activity in host and graft mesenteric lymphoid tissue of rats receiving syngeneic heterotopic small bowel allografts with portal or systemic drainage.

With the accompanying paper these studies provide further evidence that functionally important lymphoid cell trafficking takes place in mesenteric tissue under the apparent control of factor(s) filtered by hepatic tissue. The role that these regulatory mechanisms have to play on survival of vascular allografts with venous drainage into either the portal or systemic circulation remains to be elucidated.

Animals↗
PubMed1992

Altered cell trafficking in mesenteric lymphoid tissue following syngeneic heterotopic small bowel transplantation in rodents.

These data indicate that in rat heterotopic syngeneic SBT, the venous drainage system of the graft has profound effects on cell recovery in the gut-associated lymphoid tissue of both graft and host. Depending on the functional status of the same lymphoid tissue (Gorezynski, personal communication, 1992) one could thus anticipate significant perturbation of host-antigraft (and GVH) reactivity in allogeneic situations according to the venous drainage used. The mechanism(s) responsible for these effects have not been investigated. However, one testable hypothesis is that (a) factor(s) from the gut can control lymphoid recirculation within the mesenteric lymphoid tissue, and that this (these) factor(s) are absorbed under normal circumstances by hepatic tissue.

Animals↗
PubMed1991

Specific manipulation in vivo of immunity to skin grafts bearing multiple minor histocompatibility differences.

Naive CBA mice injected with AKR spleen cells via the portal vein (p.v.) subsequently showed decreased stimulation in vitro in a primary MLR or cell-mediated lympholysis assay with irradiated AKR stimulator cells. No inhibition of stimulation by B10.BR cells is seen. These mice also show specific prolongation of survival of AKR skin grafts in vivo and diminished capacity for in vivo priming for (secondary) anti-AKR responses in vitro. These effects are not seen if initial challenge is with AKR cells injected subcutaneously (s.c.) or via the lateral tail vein (i.v.). Moreover, if immune CBA anti-AKR mice are similarly challenged with AKR cells via the portal vein, no suppression of anti-AKR immunity is elicited, as determined by subsequent in vitro assays or in vivo graft rejection. However, spleen cells from CBA anti-AKR immune mice can be used to induce, in further naive CBA mice, a specific suppression of subsequent anti-AKR graft reactivity (assayed in vitro or in vivo). Active T cell-mediated suppression can be documented using both these protocols though the additional involvement of specific serum-mediated suppression cannot be eliminated.

Animals↗
PubMed1991

Toward an understanding of the mechanisms of classical conditioning of antibody responses.

Mice of different ages were subjected to repeated exposure to cyclophosphamide:saccharin (conditioned), or cyclophosphamide:saccharin followed by saccharin only (extinguished). Only young animals in the former group showed a decreased IgG antibody-forming-cell (AFC) response after challenge with sheep erythrocytes (SRBC) in the presence of saccharin. When irradiated conditioned young animals were used as recipients of antigen-challenged spleen cells from nonconditioned mice they were found to support a greater immune response than nonconditioned recipients. Similarly, cells from conditioned young mice gave a greater immune response in naive recipients than did cells from nonconditioned mice. Only when cells from conditioned young mice rather than conditioned "aged" mice were studied in irradiated conditioned young recipients was immunosuppression observed. These data are most consistent with a specific host cell:environment interaction being responsible for the conditioned immunosuppression observed in young mice. A deficit in both cells/environment apparently occurs during aging. At least one of these deficiencies seems related to loss of a suppressor T-cell population with age in conditioned mice.

Aging↗
PubMed1990

Antigenic variation in Leishmania mexicana following infection of immunized mice leads to relative sparing of suppressor determinants.

Intravenous immunization of BALB/c mice with irradiated Leishmania mexicana slows the growth of a subsequent intradermal inoculation of virulent parasites. Prior subcutaneous immunization with irradiated parasites before i.v. immunization blocks the protective effect of the latter. Parasites harvested from vaccinated mice grow more slowly in naive mice than the initial inoculated clone, and have a diminished capacity to immunize mice against this initial clone when used as (irradiated) i.v. immunogen. However, parasites harvested from vaccinated mice are as effective as the initial clone in blocking protection when used as subcutaneous immunogen. Understanding the nature of this differential response in expression of protecting/suppressor determinants in parasites harvested from vaccinated or naive mice will likely be important to developing a suitable vaccination strategy for human use.

Animals↗
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.

Animals↗
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.

Animals↗
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.

Animals↗
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.

Animals↗
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.

Animals↗
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.

Animals↗
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.

Animals↗
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.

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