Biomedical subjects

M M Kosiewicz

Publications and source records attributed to M M Kosiewicz.

6 recordsLinked to original sources

PubMed2001

Th1-type responses mediate spontaneous ileitis in a novel murine model of Crohn's disease.

We describe here the immunologic characterization of a new mouse strain, SAMP1/Yit, which spontaneously develops a chronic intestinal inflammation localized to the terminal ileum. The resulting ileitis bears a remarkable resemblance to human Crohn's disease. This strain of mice develops discontinuous, transmural inflammatory lesions in the terminal ileum with 100% penetrance by 30 weeks of age. The intestinal inflammation is characterized by massive infiltration of activated CD4+ and CD8alpha(+)TCRalphabeta(+) T cells into the lamina propria and is accompanied by a dramatic decrease in the intraepithelial lymphocyte CD8alpha(+)TCRgammadelta(+)/CD8alpha(+)TCRalphabeta(+) ratio. The results of adoptive transfer experiments strongly suggest that CD4+ T cells that produce a Th1-like profile of cytokines, e.g., IFN-gamma and TNF, mediate the intestinal inflammation found in SAMP1/Yit mice. In addition, pretreatment of adoptive transfer recipients with a neutralizing anti-TNF antibody prevents the development of intestinal inflammation, suggesting that TNF plays an important role in the pathogenesis of intestinal inflammation in this model. To our knowledge, these data provide the first direct evidence that Th1-producing T cells mediate intestinal inflammation in a spontaneous animal model of human Crohn's disease.

Adoptive Transfer↗

PubMed1998

Alterations in cytokine production following intraocular injection of soluble protein antigen: impairment in IFN-gamma and induction of TGF-beta and IL-4 production.

Immune deviation induced by intraocular injection of soluble protein Ag, referred to as anterior chamber-associated immune deviation (ACAID), is characterized by impairment of delayed hypersensitivity (DH). Two populations of splenic regulatory cells that impair the induction and expression phases of DH are involved in the ACAID response and may mediate their effects through cytokines. The purpose of the present study was to evaluate the role that cytokines play in ACAID. IFN-gamma production in draining lymph nodes induced by conventional immunization with protein Ag and adjuvant was suppressed after intraocular injection of protein Ag administered either before or after sensitization; IL-12 production in these mice was not decreased, suggesting that suppression of IL-12 may not be the mechanism involved in the impairment in IFN-gamma production. Surprisingly, although significant amounts of IL-4 (but not IL-10) were produced by spleen and lymph node cells from several different strains of mice, experiments in IL-4 knockout mice showed that impairment of neither DH nor IFN-gamma production required IL-4. Interestingly, significant levels of TGF-beta were detected in cultures of spleen cells from mice with ACAID. As determined by quantitative RT-PCR, TGF-beta was produced primarily by the splenic CD4 and non-T cells and was of the TGF-beta1 type. These results suggest that the Th1 response is impaired in ACAID by a mechanism(s) that does not require Th2-type cytokines, but may involve TGF-beta at several different (including the effector) phases during the response.

Animals↗

PubMed1997

On the mechanisms by which transforming growth factor-beta 2 alters antigen-presenting abilities of macrophages on T cell activation.

Peritoneal exudate cells (PEC) incubated with antigen in the presence of transforming growth factor-(TGF)-beta 2 selectively suppress delayed hypersensitivity and IgG2a antibody production when injected intravenously into naive syngeneic recipients. In this study, we have examined in vitro the effects of TGF-beta 2 on the antigen presenting abilities of PEC to activate DO11.10 T cells that express a transgenic T cell receptor that recognizes ovalbumin peptide fragment 323-339 in the context of I-Ad. PEC were pretreated overnight with TGF-beta 2, washed extensively, then co-cultured with DO11.10 T cells in the presence of native OVA or P323-339. We found that TGF-beta 2-treated PEC induced the production of the T helper type 2 (Th2) cytokine, interleukin-4 (IL-4), but unlike untreated PEC, were unable to stimulate the Th1 cytokines, IL-2 and interferon-gamma (IFN-gamma). Furthermore, TGF-beta 2 was produced in an autocrine fashion by TGF-beta 2-treated PEC and was responsible for this shift to a Th2 response. This conclusion was supported by the following results. First, TGF-beta 2-treated PEC were found to express much more TGF-beta 1 and TGF-beta 2 mRNA than untreated PEC. Second, TGF-beta 2-treated PEC secreted large amounts of TGF-beta including its mature form. Third, addition of neutralizing anti-TGF-beta 2 antibodies, but not neutralizing anti-TGF-beta 1 antibodies, restored the ability of antigen-pulsed, TGF-beta 2-pretreated PEC to stimulate DO11.10 T cells to secrete IL-2 and IFN-gamma. These results indicate that antigen-presenting cells that encounter antigen in a TGF-beta-enriched environment (e.g., in the eye) shift responding native T cells toward Th2 responses by producing TGF-beta during antigen presentation.

Animals↗

PubMed1996

Intraocular injection of class II-restricted peptide induces an unexpected population of CD8 regulatory cells.

Intraocular injection of exogenous protein induces an Ag-specific impairment of systemic delayed hypersensitivity (DH), termed anterior chamber associated immune deviation (ACAID). The ACAID-inducing signal is carried by blood-borne cells from the eye to the spleen and can also be generated in vitro by incubating APCs with Ag plus TGF-beta. Paradoxically, class I-restricted CD8 regulatory cells are induced in the spleens of mice with ACAID, and previous studies suggest that CD8 cells are important, and even necessary, for the expression of ACAID. To explore this issue further, we asked whether ACAID could be induced with a class II-restricted peptide, and if so, what type of regulatory cells are generated. An intraocular, but not an i.v., injection of OVA (323-339) peptide resulted in impairment of native OVA-specific DH in both naive and previously sensitized mice. Furthermore, i.v. injection of APCs pretreated with TGF-beta plus OVA peptide also prevented native OVA-specific DH. Surprisingly, both CD8+ and CD4+ spleen cells capable of impairing expression of DH were induced by either intraocular injection of peptide or i.v. injection of APCs pretreated with peptide plus TGF-beta. In summary, ACAID can be induced by a class II-restricted peptide and is accompanied by the generation of two unusual populations of cells: 1) CD8+ regulatory cells unexpectedly induced by class II-restricted peptide; and 2) a novel population of CD4 regulatory cells induced by peptide, but not native protein. Potential mechanisms involved in the processing and presentation of exogenous protein in the ACAID model are discussed in light of the present data.

Animals↗

PubMed1994

Imposing deviant immunity on the presensitized state.

Delayed hypersensitivity (DH) is an important immune effector modality that successfully wards off intracellular pathogens and many parasites, but also causes immunopathogenic injury to vital tissues. Particularly in the eye, DH has devastating effects that can lead to blindness. Ags injected into the anterior chamber of the eye of naive mice elicit a deviant form of systemic immunity in which DH is selectively down-regulated. Expression of DH in this model system is curtailed by regulatory CD8+ T cells. At present, we have determined whether injection of Ag into the anterior chamber of eyes of specifically sensitized mice also impairs DH expression. Our results indicate that DH is blunted or eliminated in previously primed mice when heterologous proteins, retinal autoantigens, or minor histocompatibility Ags are injected into the anterior chamber. Suppression is achieved in this system by Ag-specific CD8+ T cells, and failed DH can be imposed on immunized mice by i.v. injections of peritoneal exudate cells pulsed with Ag in vitro in the presence of TGF-beta. Thus, the immune regulatory mechanisms that operate to protect the eye from immunogenic inflammation can be invoked in previously sensitized mice. In addition, tolerance could not be generated in presensitized mice by either i.v. injection of soluble Ag or painting of hapten on UVB-exposed skin. It seems that the strategies used by the eye to create a deviant state of immunity in the face of pre-existing conventional immunity may be unique.

Animals↗

PubMed1990

Neonatal thymectomy affects follicle populations before the onset of autoimmune oophoritis in B6A mice.

Using a variation on a standard follicle classification technique, 5 classes of follicles were quantified in serial sections of ovaries from intact mice and mice thymectomized on Day 3 at 5-day intervals from 5 to 40 days of age. Sera from these animals and from animals 60 days of age were analysed for the presence of anti-oocyte antibodies. Ovaries from intact animals 10 to 40 days of age were examined for the presence of antigen(s) using anti-oocyte antibody-positive sera from all ages of mice. There was a dramatic decrease in the primordial follicle population at 10 days of age in thymectomized mice and that population remained significantly lower until 40 days of age. The growing follicle population was also significantly lower at 20 days of age in thymectomized mice and remained lower through 40 days of age. Anti-oocyte antibodies were not detectable until 30 days of age and at that age reacted with oocytes from all follicle types including primordial. Ovarian antigens were present in similar patterns in ovaries from mice at all ages tested. We conclude that thymectomy has an earlier influence on the ovary than previously thought and this influence does not appear to involve the immune activity associated with autoimmune ovarian dysgenesis. This suggests that the effect of thymectomy on the ovary may be biphasic: (1) an early effect, possibly involving a disruption in the hypothalamic-pituitary-ovarian-thymic axis, that influences the primordial and growing follicle populations before 20 days of age; and (2) a later effect involving an immune imbalance first evident by 25-30 days of age that ultimately results in the destruction of the ovary.

Animals↗