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Biomedical subjects

B Charlton

Publications and source records attributed to B Charlton.

At least 37 records · Page 2Linked to original sources
PubMed1995

The Th1/Th2 balance in autoimmunity.

The study of autoimmune disease in the context of T-helper type 1 (Th1) and T-helper type 2 (Th2) CD4+ T-cell responses demonstrates that the relative contribution of either T-cell type to the development of a particular autoimmune response can influence whether or not this response leads to clinical disease. Moreover, this influence can be quite different depending on whether the particular disease process is cell mediated or antibody mediated. Recent studies have demonstrated that the development of Th1 and Th2 responses may be significantly influenced by the costimulatory molecules recognized by responding CD4 T cells, and by other undefined factors in the genetic background. It has also been demonstrated that autoreactive Th2 CD4+ cells can regulate the activity of disease-causing Th1 CD4+ T cells in vivo. Control of autoimmune disease may thus be achieved by procedures that regulate the relative contribution of Th1/Th2 CD4 T cells to an autoimmune response.

Animals↗
PubMed1995

Islet-infiltrating lymphocytes from prediabetic NOD mice rapidly transfer diabetes to NOD-scid/scid mice.

In an effort to study the development of diabetes in NOD mice, our laboratory developed a novel adoptive transfer model using NOD-scid/scid (NOD-scid) mice as recipients of islet-infiltrating lymphocytes from donor prediabetic female NOD mice. We first confirmed previous results that demonstrated that splenocytes of diabetic and prediabetic female NOD mice could transfer diabetes to NOD-scid mice. We demonstrated that the kinetics of disease transfer were dependent on the age of transferred lymphocytes and reiterated the kinetics of diabetes in conventional female NOD mice. We then demonstrated that islet-infiltrating lymphocytes from prediabetic female NOD mice could transfer diabetes. In contrast with the age-dependent transfer of diabetes seen using splenocytes, islet-infiltrating lymphocytes obtained from prediabetic female NOD mice aged > or = 40 days rapidly transferred diabetes to NOD-scid recipients. The time required to transfer insulin-dependent diabetes mellitus (IDDM) using islet-infiltrating lymphocytes from young prediabetic mice (25 +/- 9 days) was not statistically different from the time required to transfer IDDM using splenocytes from overtly diabetic mice (32 +/- 5 days). Cotransfer of splenocyte cells or CD4+, but not CD8+ spleen cells, from 60- to 80-day-old prediabetic female NOD mice together with either splenocytes from diabetic mice or islet-infiltrating lymphocytes from prediabetic NOD mice delayed the rapid transfer of IDDM, suggesting that CD4+ cells mediated immunoregulation. Use of the NOD-scid islet-infiltrating lymphocyte-adoptive transfer model should help elucidate the pathophysiology of the early inflammatory events leading to insulitis and subsequent beta-cell destruction.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1994

CD4-positive/heat-stable antigen-positive thymocytes cause graft-versus-host disease across non-major histocompatibility complex incompatibilities.

Single-positive thymocytes are the immediate precursors of peripheral recent thymic emigrants (RTE) which develop into mature peripheral T cells. The functional ability of RTE is unclear but their state of differentiation may be relevant to the development of tolerance to peripheral "self" antigens. Since RTE are difficult to analyze, precursor CD4+/8- thymocytes were assessed in a model in vivo to determine their functional capability and their susceptibility to tolerance induction. The ability of both heat-stable antigen-positive (HSA+) (immature) and HSA- (mature) single-positive thymocytes to cause graft-versus-host disease (GVHD) across non-major histocompatibility complex differences were examined. Both HSA- and HSA+ CD4+/8- thymocytes from C3H mice caused lethal GVHD in AKR recipients as did CD4+ peripheral T cells in controls. Further, neonatal C3H thymocytes also caused lethal GVHD in AKR recipients. Since CD4+/8- thymocytes are the precursors of RTE, these results suggest that RTE are not susceptible to tolerance induced to "minor" antigens and may have a normal immune function in vivo. This would suggest that peripheral tolerance may be dependent upon the manner of antigen presentation rather than T cell maturity.

Animals↗
PubMed1994

Prevention of diabetes and insulitis by neonatal intrathymic islet administration in NOD mice.

The murine model of human insulin dependent diabetes mellitus (IDDM), the non-obese diabetic (NOD) mouse, develops a T cell-dependent destruction of pancreatic islets. While the target antigens are unknown, there is clearly a lack of tolerance to them. Neonatal intrathymic (i.t.) antigen injection has been successfully employed to prevent insulitis in BB rats but previous i.t. islet antigen studies in NOD mice were done on older mice. We have injected syngeneic islets into the thymus of NOD mice at birth and found that diabetes and insulitis can be completely prevented by this procedure. The effect is islet antigen-specific since other T cell responses, including autoimmune salivary infiltration, ard unaffected. Furthermore, contrary to previous studies, cyclophosphamide administration was unable to induce diabetes in treated mice which suggests that deletion or anergy might be the mechanism by which neonatal intrathymic islet injection protects from disease. However, anti-islet antigen antibodies were still present in these mice which suggests that the mechanism of disease protection may be more complex.

Animals↗
PubMed1994

Mechanisms of transplantation tolerance.

Transplantation tolerance, the long-term acceptance of grafted tissue in the absence of continuous immunosuppression, remains an elusive goal in humans, but it has been achieved in animal models using numerous approaches. The mechanisms behind graft acceptance vary according to the means used to create the state of acceptance. Several major mechanisms can now be recognized. While thymic deletion of T cells appears to be a mainstay of self-tolerance, its role in transplantation tolerance now seems to be less significant. In contrast, extrathymic mechanisms of transplantation tolerance seem to be major factors in long-term graft acceptance. If donor antigens are presented in a nonimmunogenic manner on the graft, e.g. due to modification of graft tissue by culture, peripheral T cells of the recipient may ignore the graft. Alternatively, nonstimulatory presentation of donor antigens on graft tissue can induce a state of unresponsiveness in recipient T cells, i.e. anergy, rather than activating them to destroy the graft. Suppression mechanisms also operate to control graft rejection and may be specific or nonspecific in nature. Specific suppression mechanisms might act in an idiotype or antigen-specific fashion, and evidence is accumulating that this may be mediated through the elaboration of cytokines. Donor antigen-specific T cells may be activated to produce "protective" cytokines which then regulate the generation of destructive T cells. Future therapies will be aimed at affecting graft acceptance through these peripheral mechanisms.

Animals↗
PubMed1993

Failure of a protective major histocompatibility complex class II molecule to delete autoreactive T cells in autoimmune diabetes.

The association of major histocompatibility complex genes with autoimmune diseases is firmly established, but the mechanisms by which these genes confer resistance or susceptibility remain controversial. The controversy extends to the nonobese diabetic (NOD) mouse that develops disease similar to human insulin-dependent diabetes mellitus. The transgenic incorporation of certain class II major histocompatibility complex genes protects NOD mice from diabetes, and clonal deletion or functional silencing of autoreactive T cells has been proposed as the mechanism by which these molecules provide protection. We show that neither thymic deletion nor anergy of autoreactive T cells occurs in NOD mice transgenic for I-Ak. Autoreactive T cells are present, functional, and can transfer diabetes to appropriate NOD-recipient mice.

Animals↗
PubMed1991

Intercellular adhesion molecule (ICAM-1) inhibition can induce tolerance in vivo.

Antigen specific unresponsiveness can be induced in vivo by administration of antibody against CD4, major histocompatibility complex (MHC) Class II or LFA-1 at the time of antigen exposure. Since target cell depletion is not necessary for this effect it was hypothesized that interference with intercellular interaction was responsible. To test this hypothesis, antibody against the ligand for LFA-1, ICAM-1, was administered during primary immunization with human gamma-globulin (HGG) and long-term secondary antibody responses monitored. It was found that HGG specific unresponsiveness resulted from this treatment (less than 10% of normal secondary antibody response). Delayed-type hypersensitivity responses to HGG were also suppressed suggesting unresponsiveness in some T cell subsets. These findings suggest a role for ICAM-1/LFA-1 interaction in determining the long-term outcome of contact with antigen.

Animals↗
PubMed1990

Prevention of diabetes in non-obese diabetic I-Ak transgenic mice.

The non-obese diabetic (NOD) mouse develops insulin-dependent diabetes mellitus (IDDM) with mononuclear cell infiltration of the islets of Langerhans and selective destruction of the insulin-producing beta-cells, as in humans. Most infiltrating cells are T lymphocytes, and most of these carry the CD4 antigen. Adoptive transfer of T cells from diabetic NOD mice into irradiated NOD or athymic nude NOD mice induces diabetes. Susceptibility to IDDM in NOD mice is polygenic, with one gene linked to the major histocompatibility complex class II locus, which in NOD mice expresses a unique I-A molecule but no I-E. Speculation exists as to the role of the I-A molecule in the diabetes susceptibility of NOD mice, especially regarding the significance of specific unique residues. To examine the role of the NOD I-A molecule in IDDM pathogenesis, we made NOD/Lt mice transgenic for I-Ak by microinjecting I-Ak alpha- and beta-genes into fertilized NOD/Lt eggs. Insulitis was markedly reduced and diabetes prevented in NOD/Lt mice expressing I-Ak.

Animals↗
PubMed1990

Is the peritoneal membrane durable indefinitely?

In general, the permeability characteristics of the peritoneal membrane are well maintained with time in the context of current technique survival rates. Some data would suggest that there is a tendency toward hyperpermeability in long-term PD patients; in a much smaller group of patients this may manifest itself as a loss in ultrafiltration capacity in the short term, that is within 2-4 years after CAPD initiation. A reduction in factors, which continue to have a significant negative effect upon technique survival, such as peritonitis and catheter-related infection will see patients remaining on the therapy for longer. This may place a sharper focus on ultrafiltration loss in the PD population, particularly that associated with increases in the permeability of the peritoneum. However, until such time as significant improvements occur it is likely the peritoneal membrane will continue to be more durable than the therapy in the vast majority of patients. It is now becoming clearer that the rate of decline of residual renal function (RRF) may be an important factor in the development of sequelae associated with inadequate dialysis. The role of RRF has often been overlooked when the clinical manifestations of inadequate UF and solute removal have become apparent and further study is required to determine the contribution of residual diuresis to the table of prognostic factors associated with long-term stability of the PD patient. Nevertheless, it is clearly an important parameter worthy of considerable future focus. Although membrane performance appears well maintained in general, routine monitoring of the mass transfer performance of the peritoneum should be performed. Assessment will facilitate focussed dialytic management and allow the clinician to recognise and pre-empt potential problems resulting from inadequate dialysis associated with decreasing or increasing membrane permeability in the small number of patients so affected: such monitoring should include measurement of the mass transfer coefficient at onset and every 6-12 months thereafter. However, the monitoring of RRF and overall solute clearance is perhaps of more significance in view of the contribution of RRF to overall dialytic prescription. The routine assessment of these parameters is also encouraged.

Biological Transport↗