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Biomedical subjects

A M Mowat

Publications and source records attributed to A M Mowat.

At least 37 records · Page 2Linked to original sources
PubMed1997

Mechanisms of oral tolerance.

Oral tolerance is the specific immunological unresponsiveness induced by feeding antigen. Although it is an obstacle to oral vaccination, it is probably the mechanism that prevents intestinal hypersensitivity reactions to food antigens and may provide a novel strategy for the treatment of a range of inflammatory disorders. Feeding antigen can provide stable and long-lasting tolerance of a wide range of immune responses to a variety of antigens. However, the mechanisms of oral tolerance and the major factors that influence them remain controversial.

Administration, Oral↗
PubMed1996

IL-12 is a central mediator of acute graft-versus-host disease in mice.

Distinct forms of graft-vs-host disease (GVHD) occur in (C57B1/6 x DBA/2)F1 (BDF1) mice inoculated with either C57B1/6 or DBA/2 parental spleen cells, and it has been suggested that this reflects differential activation of CD4+ Th cell subsets. Transfer of B6 cells produces an acute GVHD, during which an early period of lymphoid hyperplasia precedes immunosuppression, weight loss, and mortality, and a Th1 pattern of cytokines is produced. Conversely, transfer of DBA/2 cells induces a chronic GVHD, in which no weight loss or mortality is observed, but an autoimmune, SLE-like GVHD develops in association with a Th2 pattern of cytokines. Recent work indicates that IL-12 plays a central role in the polarization of Th cell-dependent responses, and here we have examined its role in polarizing GVHD, by administering or depleting IL-12 during the afferent phase of both the acute and chronic forms of GVHD in BDF1 mice. In vivo neutralization of endogenous IL-12 ameliorated acute GVHD, in association with reduced splenic NK cell activity, IFN-gamma production, immunosuppression, weight loss, and mortality. Conversely, administration of exogenous murine rIL-12 exacerbates this disease and converts the chronic GVHD into a lethal acute GVHD-like syndrome. These results indicate that IL-12 plays an important role in the development of acute, but not chronic, GVHD and suggest that differential production of IL-12 early in the disease may underlie these distinct outcomes of the GVHD in BDF1 mice injected with different parental cells.

Acute Disease↗
PubMed1996

Inactivation of Th1 and Th2 cells by feeding ovalbumin.

Several different mechanisms have been implicated in oral tolerance to protein antigens, depending on the nature and dose of antigen used and the species under study. Here, we have investigated the basis of unresponsiveness in a well-established model of oral tolerance in mice fed 25 mg ovalbumin (OVA). Our results show that CD8+ T-cell activity is suppressed by feeding OVA and that these cells are not required for the induction of tolerance. CD4+ T cells are essential for tolerance to occur, but both Th1 and Th2 cell-dependent functions are tolerized equally in OVA-fed mice. Peripheral lymph node cells from tolerized mice rapidly undergo apoptosis when cultured in vitro but produce substantial amounts of transforming growth factor beta (TGFbeta) in response to OVA. The appearance of tolerance in vivo is preceded by a transient phase of T-cell priming, and we propose that this model of oral tolerance reflects partial activation of T cells by fed antigen, leading to selective production of TGFbeta and consequent inactivation of all effector T cells. These findings indicate that the active suppression and clonal anergy identified previously in mice with oral tolerance may not be mutually exclusive phenomena.

Administration, Oral↗
PubMed1996

Regulatory activity of endogenous and exogenous transforming growth factor beta in experimental intestinal immunopathology.

Acute graft-versus-host disease (GvHD) is an inflammatory disorder associated with generalised damage to epithelial tissues, including the gastrointestinal tract. There is increasing evidence that this pathology is due to the effects of cytokines on epithelial cell proliferation and differentiation. However, it is unclear whether factors derived from immune cells act directly on epithelial cells or via other mediators whose principal role is to regulate cell growth under normal or diseased conditions. We show here that the increased crypt cell turnover and lymphocytic infiltration which occurs in the jejunum of mice with graft-versus-host reaction (GvHR) is accompanied by decreased enterocyte expression of transforming growth factor beta 2. Administration of exogenous TGF beta inhibits the crypt hyperplasia of GvHR and reduces systemic manifestations of GvHR such as increased splenic natural killer (NK) cell activity. In parallel, neutralisation of endogenous TGF beta by monoclonal antibody exacerbates both the proliferative and inflammatory components of intestinal and systemic GvHR. Thus, the immune system may induce epithelial pathology at least in part by altering the production of endogenous TGF beta. This cytokine may therefore prove a useful focus for therapeutic intervention in immunopathologies such as GvHD.

Animals↗
PubMed1996

Lymphocytes from orally tolerized mice display enhanced susceptibility to death by apoptosis when cultured in the absence of antigen in vitro.

The mechanism responsible for the induction of immunological tolerance by oral administration of soluble antigen remains unclear. Here we show that, when cultured in vitro in the absence of antigen, lymphocytes from mice tolerized with a single feed of 25 mg of ovalbumin display an enhanced mortality in comparison with cells from immunized control animals. This increased cell death affects both CD4+ and CD8+ T-lymphocyte subsets, and morphological and flow cytometric analyses suggest that it occurs via apoptosis. All of the changes associated with the propensity of tolerant cells to die by apoptosis in vitro are reduced by the inclusion of the tolerizing antigen in the cultures. These results suggest that tolerance to dietary proteins is accompanied by functional changes in T lymphocytes that render them susceptible to apoptosis. This mechanism may underlie the profound and permanent tolerance to food antigens found under physiological conditions and may provide a useful basis for immunotherapy.

Administration, Oral↗
PubMed1995

T helper 2 cells are subject to high dose oral tolerance and are not essential for its induction.

Oral administration of aqueous protein Ag results in profound immunologic tolerance, and it has been suggested previously that this reflects selective activation of Th subsets. Here we show that the induction of oral tolerance by feeding a single high dose of OVA to mice significantly reduces the production of both Th1- and Th2-dependent cytokines and is accompanied by a marked reduction of specific Abs of both the IgG2a and IgG1 isotypes in vivo. Oral tolerance was also induced normally in IL-4-deficient mice. These results indicate that both subsets of the Th cell are equally susceptible to the induction of tolerance with a single high dose of Ag delivered via the oral route and that this phenomenon does not require Th2 cells.

Administration, Oral↗
PubMed1995

Induction of Th1 and Th2 CD4+ T cell responses by oral or parenteral immunization with ISCOMS.

We examined the ability of oral or parenteral immunization with immune stimulating complexes containing ovalbumin (ISCOMS-OVA) to prime T cell proliferative and cytokine responses. A single subcutaneous immunization with ISCOMS-OVA primed potent antigen-specific proliferative responses in the draining popliteal lymph node, which were entirely dependent on the presence of CD4+ T cells. CD8+ T cells did not proliferate in vitro even in the presence of the appropriate peptide epitope and exogenous interleukin (IL)-2. Primed popliteal lymph node cells produced IL-2, IL-5 and interferon (IFN)-gamma, but not IL-4 when restimulated with OVA in vitro. Serum antigen-specific IgG1 and IgG2a antibody responses were also primed by subcutaneous immunization with ISCOMS-OVA, confirming the stimulation of both Th1 and Th2 cells in vivo. Spleen cells from subcutaneously primed mice produced a similar pattern of cytokines, indicating that disseminated priming had occurred. Oral immunization with ISCOMS-OVA also primed local antigen-specific proliferative responses in the mesenteric lymph node and primed an identical pattern of systemic cytokine responses in the spleen. The ability of ISCOMS to prime both Th1 and Th2 CD4+ T cell responses may be central to their potent adjuvant activities and confirm the potential of ISCOMS as future oral vaccine vectors.

Administration, Oral↗
PubMed1995

Polarization of Th-cell responses: a phylogenetic consequence of nonspecific immune defence?

CD4+ T helper (Th)-cell responses are polarized into Th1 and Th2 types. Here, Paul Garside and Allan McI. Mowat propose that this is an evolutionary consequence of the relationship between specific adaptive immunity, individual components of the nonspecific inflammatory response and different types of infection. This concept has important implications both for understanding protective immunity and for vaccine design and delivery.

Animals↗
PubMed1995

CD4+ but not CD8+ T cells are required for the induction of oral tolerance.

It has been suggested that oral tolerance is mediated by CD8+ T lymphocytes, but the functional properties of these cells are unclear. Here we show that the induction of tolerance by feeding mice ovalbumin (OVA) does not prime antigen-specific class I MHC-restricted cytotoxic T cells in vivo. Indeed, such responses are markedly suppressed in mice fed OVA, and the induction of oral tolerance is abolished by depletion in vivo of CD4+ but not CD8+ T cells. These results indicate that CD8+ lymphocytes are unlikely to play a major role in the induction of oral tolerance and are the first demonstration that specific cytotoxic responses to an exogenous antigen can be suppressed by feeding antigen.

Administration, Oral↗
PubMed1995

A role for IL-4 in immunologically mediated enteropathy.

A number of clinical enteropathies are associated with a local cell-mediated immune (CMI) response, and experimental evidence indicates that cytokines are responsible for the intestinal pathology. We show here that depletion of IL-4 using MoAb or a soluble form of the IL-4 receptor (IL-4R) prevents the jejunal manifestations of a proliferative form of murine graft-versus-host reaction (GVHR) characterized by crypt hyperplasia and recruitment of intraepithelial lymphocytes (IEL). Depletion of IL-4 did not prevent the appearance of villus atrophy in a destructive model of GVHR, and had no effect on any indices of systemic immunity. These results indicate that IL-4 may play a selective role in mediating proliferative aspects of intestinal immunopathology, and suggest that this cytokine may provide a useful target for immunotherapy.

Animals↗
PubMed1994

Induction of mucosal and systemic immune responses by immunization with ovalbumin entrapped in poly(lactide-co-glycolide) microparticles.

We have examined the range of mucosal and systemic immune responses induced by oral or parenteral immunization with ovalbumin (OVA) entrapped in poly(D,L-lactide-co-glycolide) (PLG) microparticles. A single subcutaneous immunization with OVA-PLG primed significant OVA-specific IgG and delayed-type hypersensitivity (DTH) responses. The DTH responses were of similar magnitude to those obtained using immunostimulating complexes (ISCOMS) as a potent control adjuvant, although ISCOMS stimulated higher serum IgG responses. Both vectors also primed OVA-specific in vitro proliferative responses in draining lymph node cells following a single immunization and strong OVA-specific CTL responses were found after intraperitoneal (i.p.) immunization. ISCOMS were more efficient in inducing cytotoxic T lymphocytes (CTL), requiring much less antigen and only ISCOMS could stimulate primary OVA-specific CTL responses in the draining lymph nodes. Multiple oral immunizations with OVA in PLG microparticles or in ISCOMS resulted in OVA-specific CTL responses and again ISCOMS seemed more potent as fewer feeds were necessary. Lastly, multiple feeds of OVA in PLG microparticles generated significant OVA-specific intestinal IgA responses. This is the first demonstration that PLG microparticles can stimulate CTL responses in vivo and our results highlight their ability to prime a variety of systemic and mucosal immune responses which may be useful in future oral vaccine development.

Adjuvants, Immunologic↗
PubMed1994

Differential cytokine production associated with distinct phases of murine graft-versus-host reaction.

Previous studies which demonstrated that cytokines such as interferon-gamma (IFN-gamma) and tumour necrosis factor-alpha (TNF-alpha) are essential for the development of graft-versus-host reaction (GvHR) did not establish whether the individual cytokines were responsible for distinct features of the disease. In this report, we show that IFN-gamma production is associated with the early proliferative phase of the disease, whereas the late, destructive phase correlates with production of TNF-alpha. These studies may assist in the development of specific immunotherapies aimed at individual aspects of immunologically mediated disease.

Animals↗
PubMed1993

Biodegradable microparticles for oral immunization.

Ovalbumin (OVA) was entrapped in poly(lactide-co-glycolide) microparticles and administered to mice. Following intraperitoneal immunization, the microparticles induced both proliferative T-cell responses and cytotoxic T-cell responses in spleen cells. Following oral immunization, the mean salivary IgA antibody response to microparticles was significantly greater than the response to soluble OVA (p < 0.0001). Serum IgG antibody levels were also significantly greater in the group administered microparticles (p < 0.001). Cholera toxin B subunit was also entrapped in microparticles. Following oral immunization in mice, specific antibody-secreting cells were detected both in the spleens and in the mesenteric lymph nodes.

Administration, Oral↗
PubMed1993

Analysis of enteropathy induced by tumour necrosis factor alpha.

Tumour necrosis factor (TNF)-alpha has been implicated in the pathogenesis of experimental and clinical enteropathy, but its exact role is unknown. We show here that a single dose of TNF-alpha causes significant small intestinal pathology in normal adult mice, which develops within 15 minutes, persists for up to 48 hours and is enhanced by interferon-gamma (IFN-gamma). The enteropathy consists of villus atrophy and crypt hyperplasia and is therefore similar to that found in immunologically mediated enteropathies such as graft-versus-host reaction (GvHR). TNF-alpha is also cytotoxic to an intestinal crypt cell line in vitro. Thus, a direct action of TNF-alpha on crypt cells may be involved in its enteropathic effects in vivo. Together, these findings indicate that TNF-alpha alone, or in concert with other cytokines, may be an important effector molecule in immunologically mediated intestinal pathology and may ultimately provide a target for specific immunotherapy for clinical enteropathies.

Animals↗