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Biomedical subjects

B Charlton

Publications and source records attributed to B Charlton.

At least 19 recordsLinked to original sources
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↗
PubMed1989

Tolerance to aggregated human IgG but not ovalbumin can be induced by concurrent administration of depleting or non-depleting anti-L3T4 monoclonal antibodies.

Tolerance to soluble antigens has previously been shown to occur in mice if anti-L3T4 monoclonal antibody (MoAb) is administered at the time of antigen exposure. The process of tolerance induction may require the depletion of L3T4+ cells or it may be due to down-regulation or negative signalling of L3T4+ cells. We compared the effects of L3T4+ cell depletion and L3T4 antigen blockade at the time of primary antigen challenge on long-term humoral responses. Anti-L3T4 MoAb GK1.5 (IgG2b) and H129.19 (IgG2a) were used to deplete or block, respectively, L3T4+ cells. Following a short course of MoAb and antigen challenge with both aggregated human IgG (ag-HGG) and ovalbumin (OVA) in each mouse, primary response titres to each antigen in both MoAb treated groups were approximately 1:10(2) compared with approximately 1:10(5) in control mice. Repeated antigen challenge significantly increased the anti-OVA titre in both MoAb treated groups and by 150 days they were similar to controls. However, anti-HGG titres did not increase significantly in either of the MoAb treated groups. Thus either depletion of peripheral L3T4+ cells, or blockade of the L3T4 antigen without depletion of peripheral L3T4+ cells, can invoke a state of long-term antigen-specific tolerance to some antigens. Why the effect is restricted to particular antigens, and the exact mechanisms of tolerance induction remain to be determined.

Animals↗
PubMed1989

An increase in the survival of murine H-2-mismatched cultured fetal pancreas allografts using depleting or nondepleting anti-CD4 monoclonal antibodies, and a further increase with the addition of cyclosporine.

Depletion of CD4+ T lymphocytes with monoclonal antibodies (mAbs) has been shown to prolong allograft survival in mice. In this study, two rat anti-CD4 mAbs, H129.19 and GK1.5, were administered either alone or in combination with cyclosporine (CsA) to recipients of MHC-mismatched (H-2k to H-2d) cultured fetal pancreas allografts to determine their effect on graft survival. When compared with control mice, splenic CD4+ cells of GK1.5-treated mice were depleted by greater than 95%, but in H129.19-treated mice no depletion of CD4+ cells occurred. Instead, rat Ig was present on the surface of CD4+ cells in H129.19-treated mice. Anti-CD4 therapy with either H129.19 or GK1.5 prolonged fetal pancreas allograft survival to a similar extent, but did not lead to indefinite survival. Blockade of the CD4 antigen by the mAb H129.19 was as effective as the depletion of CD4+ cells by GK1.5 in prolonging allograft survival. Rejection of grafts by day 28 posttransplantation occurred in the absence of CD4+ cells, as determined by both flow cytometric examination of spleen cells and immunoperoxidase staining of the graft site. CsA alone did not prolong graft survival, but its addition to either H129.19 or GK1.5 mAb treatment significantly increased the survival rate of grafts at 28 days compared with mAb treatment alone. These results suggest that CD4+ cell depletion is not essential for effective anti-CD4 mAb therapy--and, further, that CsA may have a direct inhibitory effect on CD8+ cells during allograft rejection.

Animals↗
PubMed1989

Prevention of cyclophosphamide-induced diabetes by anti-V beta 8 T-lymphocyte-receptor monoclonal antibody therapy in NOD/Wehi mice.

Walter & Eliza Hall Institute nonobese diabetic (NOD/Wehi) mice exhibit a low incidence of spontaneous diabetes mellitus, but one large dose of cyclophosphamide (CY) can lead to a rapid progression to overt diabetes. Macrophages and Lyt-2+ and L3T4+ cells have been demonstrated to be involved in beta-cell destruction in this model. The role of a specific subset of T-lymphocytes expressing a particular T-lymphocyte-receptor segment was examined in CY-induced diabetic NOD mice with a mouse anti-V beta 8 T-lymphocyte-receptor monoclonal antibody (F23.1). After administration of CY, only 4 of 51 treated mice became hyperglycemic compared to 23 of 47 untreated mice, 13 of 26 mice treated with an isotype-matched control ascites, and 4 of 6 mice given antibody-negative ascites. Insulitis was significantly reduced in the F23.1-treated group, and immunocytochemistry revealed the absence of V beta 8 expression on cells in the lymphoid organs and insulitis of these mice. This investigation revealed that V beta 8+ cells were implicated in CY-induced diabetes in NOD/Wehi mice.

Animals↗
PubMed1989

Cyclophosphamide-induced diabetes in NOD/WEHI mice. Evidence for suppression in spontaneous autoimmune diabetes mellitus.

Nonobese diabetic (NOD) mice spontaneously develop a lymphocytic infiltration of pancreatic islets (insulitis) that may progress to overt diabetes. Virtually all NOD/WEHI mice develop insulitis, but very few progress to diabetes. However, cyclophosphamide (CY) can promote the onset of diabetes in NOD mice, including the NOD/WEHI strain. The means by which CY produces diabetes was investigated in NOD/WEHI mice, in which it was hypothesized that active suppression mechanisms prevented the progression from insulitis to diabetes. A study of the time course of insulitis in the islets after CY was given showed that insulitis was initially reduced but rapidly increased over 16 days, and T-lymphocytes were predominant in the lesion. This suggested a compression of the normal time course of the disease seen in NOD mice. CY did not produce diabetes in any of 11 non-NOD strains studied. Fetal isografts in NOD mice given CY several days before were subjected to lymphocytic infiltration and beta-cell destruction. These findings suggested that CY was not directly beta-cell toxic and that altered beta-cells were not essential for beta-cell destruction. This was further demonstrated with subdiabetogenic doses of streptozocin, which significantly damaged beta-cells but did not increase the severity of insulitis or induce diabetes as did CY. Most important, the transfer of mononuclear cells from nondiabetic NOD mice to mice given CY prevented diabetes, which indicated that the likely effect of CY was via immunomodulation, possibly by allowing poised effector cells to act on beta-cells.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1989

Recurrence of insulitis in the NOD mouse after early prolonged anti-CD4 monoclonal antibody treatment.

The treatment of young NOD mice with continuous anti-CD4 mAb administration has previously been shown to prevent insulitis from developing. It has also been shown that insulitis, once present, can be abolished by anti-CD4 mAb treatment, but that the insulitis recurs after treatment stops. We have studied the effect of treating young NOD/Wehi mice with a limited course of anti-CD4 mAb to determine if any long term prevention of insulitis ensued. Anti-CD4 mAb (H129.19) was given i.p. weekly to 10 female NOD/Wehi mice from 25-100 days of age. Control mice received no treatment. The pancreas of the mice were examined histologically at 100 and 180 days of age and severity of insulitis graded from 0-100%. The insulitis grade in treated mice at 100 days was 5 +/- 2% compared with 29 +/- 26% in age matched control mice (p less than 0.01). At 180 days of age the insulitis grade in treated mice was 29 +/- 23% compared with 47 +/- 22% in aged matched controls (NS). Thus insulitis was prevented from developing by early treatment with anti-CD4 mAb but developed later when treatment was stopped. Early anti-CD4 mAb treatment does not therefore appear to produce a tolerant state so averting insulitis development and, insulitis can still develop in older NOD mice.

Animals↗