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Biomedical subjects

T E Mandel

Publications and source records attributed to T E Mandel.

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

The effect of a depleting anti-CD4 monoclonal antibody on T cells and fetal pig islet xenograft survival in various strains of mice.

The effect of a cell-depleting anti-CD4 monoclonal antibody (mAb), GK1.5, was studied in a number of strains of inbred mice. Young adult female NOD/Lt, CBA and BALB/c mice were transplanted with organ cultured fetal pig pancreas and given 0.3 mg of the mAb (as ascites) on days -1, 0 and +1. The grafts were mostly rejected within 13 days in CBA mice but BALB/c and NOD recipients still had essentially intact grafts with the NOD mice showing evidence of early rejection. By 28 days posttransplantation the BALB/c recipients still had well-preserved grafts with minimal infiltration, but NOD and CBA mice had generally rejected their grafts totally. Peritransplant mAb treatment reduced CD4+ T cells in the spleen and they showed only incomplete recovery by 28 days. To further analyse the effect of anti-CD4 treatment, these strains as well as C57BL/6 mice were given a single dose (0.3 mg) of GK1.5 either as ascites or as affinity purified mAb. There was no obvious difference in effect between the ascites and the purified mAb within a strain but the various strains showed consistent differences in their blood, spleen and lymph node lymphocytes and in their response to the mAb. C57BL/6 mice differed from the other strains in having fewer T cells but more B cells in the blood, spleen and lymph nodes and a low CD4/CD8 ratio. Recovery of CD4+ T cells was most rapid in NOD mice and this together with the relatively high number of these cells may account for the ability of these mice to reject grafts despite immunosuppression that can allow prolonged graft survival in other strains. This study emphasizes the need to examine various strains of mice when making general statements about the efficacy of immunosuppression in transplantation and stresses the need to be aware of the frequent use of 'permissive' strains in reports where excellent graft survival is reported.

Animals↗
PubMed1995

Induction of insulitis in athymic (nude) mice. The effect of NOD thymus and pancreas transplantation.

The NOD mouse is a model for human insulin-dependent diabetes mellitus. The disease is thought to have an autoimmune etiology because it is T-cell dependent and is characterized by mononuclear cell infiltration in and around the pancreatic islets of Langerhans. The mechanism by which autoreactive T-cells are generated is not fully understood, but it has been postulated that there is a breakdown in self-tolerance induction during intrathymic T-cell maturation. The aim of these studies was to determine whether transplantation of NOD thymus into diabetes-resistant mouse strains would generate islet-reactive T-cells. Neonatal thymus was pretreated either by irradiation or culture in 2-deoxyguanosine (dGua) and then transplanted into athymic BALB/c, CBA, and C57BL/6 nude mice. Generally, insulitis was not seen in the CBA or C57BL/6 recipients, but was found in 56% of BALB/c mice transplanted with an irradiated NOD thymus and in 46% BALB/c mice with a dGua-treated thymus. Similar experiments in which a NOD fetal pancreas was transplanted into nude BALB/c mice before NOD thymus transplantation showed a similar frequency and severity of insulitis in both the host pancreas and grafted NOD pancreas. This suggests that NOD islets are no more prone than the host islets to autoimmune attack and do not exacerbate insulitis. Overall, the data suggest that a defect of thymic origin (and correlating with the thymic epithelium) in the NOD mouse can lead to the development of autoreactive T-cells and specific islet cell damage. Autoreactivity appears to be restricted to the H-2Kd allele that is shared by NOD and BALB/c mice.

Animals↗
PubMed1995

Prevention of autoimmunity in nonobese diabetic (NOD) mice by neonatal transfer of allogeneic thymic macrophages.

Nonobese diabetic (NOD) mice spontaneously develop insulin dependent diabetes mellitus. The disease results from an autoimmune process which involves mononuclear cells surrounding and eventually infiltrating the pancreatic islets of Langerhans. Macrophages are thought to be the first cells to infiltrate the islets and are actively involved in the disease process because diabetes is prevented if host macrophages are depleted or inactivated. Several lines of evidence also suggest that NOD macrophages are phenotypically and functionally abnormal. In this study, allogeneic (CBA) macrophages derived from the thymus were inoculated into newborn NOD mice and these were followed for more than 250 days. Spontaneous diabetes was significantly reduced in female NOD mice (6% diabetic versus 45% of controls). Insulitis was also significantly reduced in both male and female mice compared to their control counterparts, and in most cases there were virtually no inflammatory cells in the pancreas. Allogeneic skin grafting and mixed leukocyte cultures indicated that the recipients were not tolerant of donor antigens, and donor-derived cells were not detected in the lymphoid tissues by either flow cytometry or immunohistochemistry. The results show that macrophages from diabetes-resistant donors will prevent insulitis and diabetes in most recipients, however, the mechanism for the protection is unclear, but does not appear to be due to long-term tolerance induction.

Animals↗
PubMed1995

A comparison of organ cultured fetal pancreas allo-, iso-, and xenografts (pig) in non-immunosuppressed non-obese diabetic mice.

The response of non-immunosuppressed non-obese diabetic/Lt mice to an isograft (H-2g7), major histocompatibility complex-mismatched allografts (CBA, H-2K; BALB/c, H-2d), and xenograft of fetal pig pancreas was assessed by light microscopy. In non-obese diabetic mice, isografts were rapidly invaded by lymphoid cells, and the graft pathology was similar to that in the host pancreas. In prediabetic mice the graft site was invaded by small mononuclear cells (CD4 and CD8+ve T cells) and macrophages, and in diabetic mice specific beta-cell destruction was found. The allografts were invaded and destroyed within 10 to 14 days by mononuclear cells that included many blast cells. In the allograft sites the infiltrating cells soon disappeared, and within 3 weeks only a scar remained. The xenografts, in contrast, were invaded by macrophages and eosinophils with some neutrophils and mast cells and multinucleated giant cells. Xenograft destruction also occurred over 8 to 10 days, but the site remained large and swollen with a central necrotic zone and massive fibrosis forming a large granuloma, and the infiltrate persisted for many weeks. Thus, there are marked differences in the host response to a challenge with tissue that is prone to cell-specific autoimmune disease, to a graft of immunogenic allogeneic tissue, and to a transplant of discordant xenogeneic islets. Because of the differences in the host response to these grafts different immunosuppressive strategies may be needed to cope with their destruction.

Animals↗
PubMed1994

A comparison of corneal, pancreas, and skin grafts in mice. A study of the determinants of tissue immunogenicity.

A model of murine heterotopic allogeneic transplantation was used to study the rejection characteristics of three tissues--adult cornea, fetal pancreas, and fetal skin--for attributes that might explain their variation in rejection rates and help define the determinants of graft immunogenicity. Under identical conditions, tissues were transplanted to the renal subcapsular space and their base-line rejection rates compared. The expression of MHC class I and II and intercellular adhesion molecule-1 (ICAM-1), was determined for each tissue, as was their ability to produce interleukin-6, IL-3, interferon-gamma, and granulocyte-macrophage colony-stimulating factor in vitro. These studies were performed under basal conditions and after stimulation with concanavalin A-stimulated spleen cell supernatant (CAS) or INF gamma. Corneal grafts had a slow rejection rate compared with pancreas and skin. While all three tissues had low basal expression of MHC class II, both fetal skin and pancreas, but not adult cornea, were able to increase this under our experimental conditions. Pancreas and skin produced IL-6 under basal conditions and could be stimulated to increase production 2-3-fold but the cornea did not basally produce IL-6 and showed minimal upregulation. We postulate that delayed corneal rejection, compared with pancreas and skin, results from two compounding deficiencies: the relative lack of class II MHC-positive APC and the inability to overcome this deficiency by upregulating class II expression and producing accessory molecules for antigen presentation.

Animals↗
PubMed1994

Lymphocyte subsets in thymus and peripheral lymphoid tissues of aging and diabetic NOD mice.

The nonobese diabetic (NOD) mouse spontaneously develops insulin dependent diabetes mellitus. The disease is associated with a leucocytic infiltration of the pancreatic islets of Langerhans and it is believed that during the development of autoimmune diabetes, the insulin-secreting islet beta-cells are destroyed by autoreactive T lymphocytes. We investigated the alteration of lymphocyte subsets in central and peripheral lymphoid organs of NOD female mice with increasing age beginning before the onset of insulitis and ending well after the onset of diabetes. The spleen, inguinal and pancreatic lymph nodes all increased in cell number, especially after the onset of insulitis (8 weeks), and all decreased after the onset of diabetes. Flow cytometric studies showed a widening of the visible side scatter profile of female NOD lymph node cells which coincided with the initiation of insulitis. Anti-CD4 and anti-CD8 double staining of thymocytes revealed a large increase in the double negative population and a corresponding decrease in the double positive population, but this occurred long after the onset of diabetes. Generally, there was an increase in the CD4:CD8 ratio in the peripheral lymphoid organs during the onset of insulitis which was largely due to an increase in the CD4 T cell population while the ratio decreased after the onset of diabetes. In the spleen this was mostly due to an increase in CD8 T cells. The pancreatic lymph nodes, which theoretically might reflect what is happening in the pancreas, showed an unexpected decrease in overall cell number and a decrease in T-cells (especially CD4 T cells), while B cells were increased.(ABSTRACT TRUNCATED AT 250 WORDS)

Age Factors↗
PubMed1993

Future directions in transplantation.

Transplantation has become an established treatment for many diseases where organ replacement is the best or perhaps the only option, but it has not reached its full potential. The use of fetal and infant donors raises ethical problems, as does the use of other species for xenografts. Legal problems include the drafting of appropriate legislation to maximise the donor pool. Economic limitations are imposed by the competition for funding with other areas of medicine. Transplantation of cells, tissues, and organs is rapidly being expanded. Exciting progress in experimental models of new methods of immunosuppression may lead to immunological tolerance of grafts so that chronic non-specific immunosuppression becomes a thing of the past. Xenografts will probably have to become a major source of organs as transplantation is extended to more patients and a broader range of diseases. Genetic engineering may alleviate the problem of supply in some instances; free cell transplants of genetically modified cells are being studied.

Ethics, Medical↗
PubMed1993

Immunosuppressive antibody treatment prolongs graft survival in two murine models of segmental pancreas transplantation.

Successful pancreas transplantation requires the suppression of both allograft rejection and recurrence of autoimmune disease. In order to study treatments to suppress these two responses, separate models were developed for pancreas allograft rejection and autoimmune disease. In the first model, the diabetic state was induced with streptozotocin in CBA mice prior to the transplantation of pancreas grafts from BALB/c donors. In the absence of autoimmune disease, control mice rejected their grafts in 26 days (median). Antibody treatments (anti-lymphocyte serum and anti-CD4) significantly prolonged allograft survival beyond this time, but not to the extent we have previously reported in the heart graft model. NOD/Lt mice spontaneously developed autoimmune diabetes, and recurrence of disease was seen in isografts at 9.5 days (median). Antibody treatments significantly delayed disease recurrence, with anti-CD4 being the most effective. Heart allografts (CBA donors) in NOD/Lt recipients were rejected within 17 days (median), and the anti-CD4 treatment had a moderate effect in delaying graft survival (median 28 days). Anti-lymphocyte serum did not prolong graft survival. Thus antibody treatment was effective in delaying both rejection and the recurrence of autoimmune disease in segmental pancreas grafts. However, the same doses were not effective in delaying heart rejection in the NOD/Lt model, so it would appear that treatments which inhibit autoimmune disease may not prevent allograft rejection.

Animals↗
PubMed1993

Urocanic acid as an immunosuppressant in allotransplantation in mice.

Urocanic acid (UCA) was investigated for its activity as an immunosuppressive agent in murine heterotopic allotransplantation. Mice grafted with cornea, pancreas, and skin under the renal capsule were given either intravenous, subcutaneous, or topical cis-UCA in the peritransplant period. Grafts were performed across complete and minor MHC barriers. Peritransplant immunosuppression with cis-UCA prolonged survival of these grafts, but no route of administration was clearly superior to another. Survival of cornea was prolonged more than survival of skin or pancreas in all MHC disparate combinations. cis-UCA was also used to assess its effect on stimulator cells, derived from mice that had received UCA, in mixed lymphocyte responses. cis-UCA adversely affected the ability of stimulator cells to provoke T cell proliferation in an allogeneic MLR. These findings suggest that cis-UCA may be a potentially useful immunosuppressive agent.

Animals↗
PubMed1993

Genetic basis for diabetes resistance in NOD/Wehi mice.

The basis for diabetes resistance in low diabetes incidence NOD/Wehi mice was examined in a breeding study. NOD/Wehi mice were crossed with high diabetes incidence NOD/Lt mice producing F1 hybrid mice which expressed a low incidence of diabetes. To distinguish between genetic and environmental causes for diabetes resistance, these F1 mice were backcrossed to NOD/Lt mice resulting in BC1 hybrid mice which expressed an intermediate incidence of diabetes. Similar results were obtained by examining the severity of insulitis in the hybrid mice. As both the incidence of diabetes and severity of insulitis in the hybrid mice were consistent with a single dominant gene mediating diabetes resistance, an attempt to localize this gene was made. Although over 140 loci which display polymorphism amongst inbred strains were typed in both parental lines, only a single locus, D8Mit9, was found to differ. As heterozygotes at D8Mit9 were not over represented amongst 45 diabetic BC1 hybrid mice examined, it was concluded that a resistance gene was not linked to this locus.

Alleles↗
PubMed1993

The effect of cyclophosphamide treatment on lymphocyte subsets in the nonobese diabetic mouse: a comparison of various lymphoid organs.

The nonobese diabetic (NOD) mouse is a model for human Type 1 diabetes mellitus. Pancreatic beta-cell destruction in NOD mice is mediated by an autoimmune process which can be accelerated by cyclophosphamide (CP). We studied the phenotype of lymphocytes from central, peripheral and regional lymphoid tissues in prediabetic NOD and C3H mice before and after a single large dose of CP. All lymphoid organs showed a greatly diminished cell number and most alterations appeared early after CP and were transient, but an aggressive insulitis was not seen in NOD mice until 14 d after injection. The pancreatic islets in C3H mice remained intact and were not infiltrated. NOD female mice, which are most prone to spontaneous and CP-induced diabetes, exhibited the most unusual lymphoid kinetics after treatment with CP. Their thymus and spleen showed the least relative drop in total cell number and the most rapid rate of recovery. The thymus of these mice was also found to have an increased proportion of CD3+ thymocytes while CD4/CD8 double positive thymocytes decreased 7 d after CP. At 14 d after CP the number of IL-2R+ thymocytes had surpassed that of normal levels. The most dramatic observation was the rapid recovery and overshoot in the number of pancreatic lymph node cells of female NOD mice which coincided with aggressive insulitis.

Animals↗