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Query: UMLS:C0011849 (diabetes)
 277,896 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Pancreatic tissue grafting is by far the most physiological therapeutic solution to the insulin deficiency of diabetes. Recent clinical trials have indicated somewhat successful use of nonsteroidal immunosuppressive regimens and a successful nonhuman primate trial using CD154 for costimulation blockade was reported. However, these protocols need to be replaced with safe and efficacious ones in which long-term allotolerance would make these treatments routine in a clinical setting. With the specific objective of testing whether peripheral infusions of stem cells or stem cell fractions in conjunction with islet allografting would induce allograft tolerance, we have established a macaque diabetic model. The macaques were rendered diabetic by streptozotocin and required daily doses of insulin to maintain lower blood glucose levels. The diabetic macaques then received islets and stem cells from unrelated and MHC-mismatched donors without any immunosuppression. In our initial analysis, 5 of 7 macaques that received stem cell infusions at the time of islet allografting have shown allograft survival longer than the group of macaques that received islets without the stem cell infusion. One of these five macaques has been normoglycemic for 10 months, with no exogenous insulin. This macaque received stem cell population enriched for CD34+ cells with depletion of CD18 cells, which have shown low or no allostimulatory potential in mixed lymphocyte cultures. Increased levels in insulin and C-peptide levels were shown in the macaques after islet transplantation.
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PMID:Induction of donor-specific tolerance to islet allografts in nonhuman primates. 1202 Nov 5

We followed the fate of K(d)- or I-A(g7)-restricted beta cell-autoreactive T cells in monoclonal TCR-transgenic NOD mice expressing or lacking CD154. 8.3-NOD.RAG-2(-/-)/CD154(-/-) mice, which bear autoreactive CD8(+) T cells, developed diabetes with the same incidence and tempo as 8.3-NOD.RAG-2(-/-)/CD154(+) mice. Recruitment of CD154(-/-) 8.3-CD8(+) CTL was accelerated by CD154(+)CD4(+) T cells, by expression of a B7.1 transgene in beta cells or by treatment of the mice with CpG-DNA or an agonistic anti-CD40 antibody. In contrast, the autoreactive CD4(+) T cells maturing in 4.1-NOD.RAG-2(-/-) mice lost their diabetogenic potential if they lacked CD154, even in the presence of CD154(+)CD4(+) T cells, B7.1 molecules on beta cells, CpG-DNA treatment, or systemic CD40 ligation. These results demonstrate the existence of a novel, CD154-dependent pathway of CD4(+) T cell activation that is independent of CD40-mediated activation of APCs.
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PMID:CD154-dependent priming of diabetogenic CD4(+) T cells dissociated from activation of antigen-presenting cells. 1204 23

Although it has often been assumed that transplanted allogeneic islets can be destroyed by recurrent autoimmunity in recipients with type 1 diabetes, definitive evidence is lacking and the settings in which this may occur have not been defined. To address these issues, we compared the survival of islet transplants (subject to tissue-specific autoimmunity) with cardiac transplants (not subject to tissue-specific autoimmunity) from various major histocompatibility complex (MHC)-matched and -mismatched donors transplanted into autoimmune NOD recipients. We found that when recipients were treated with combined B7 and CD154 T-cell costimulatory blockade, hearts survived best with better MHC matching, whereas islets survived worst when the donor and recipient shared MHC class II antigens. In the absence of full or MHC class II matching, there was no difference in the survival of islet and cardiac allografts. We also found that the tendency of NOD mice to resist tolerance induction by costimulation blockade is mediated by both CD4+ and CD8+ T-cells, not directly linked to the presence of autoimmunity, and conferred by non-MHC background genes. These findings have clinical importance because they suggest that under some circumstances, avoiding MHC class II sharing may provide better islet allograft survival in recipients with autoimmune diabetes, since mismatched allogeneic islets may be resistant to recurrent autoimmunity. Our results may have implications for the design of future clinical trials in islet transplantation.
Diabetes 2002 Nov
PMID:The role of autoimmunity in islet allograft destruction: major histocompatibility complex class II matching is necessary for autoimmune destruction of allogeneic islet transplants after T-cell costimulatory blockade. 1240 11

The autoimmune diabetes of the DRBB rat shares important similarities with autoimmune diabetes in humans. We have tested the ability of CD40/154 blockade using an anti-CD154 antibody (AH.F5) to prevent autoimmune diabetes in DRBB rats. The rats were treated with two intravenous doses/wk of AH.F5 (15mg/kg/dose) starting at 2-6wks of age. RT6.1 T-cell depletion and poly I/C was started at 4wks of age. Control rats developed diabetes within 25 days after start of depletion therapy. Six of 7, 11 of 13, 7 of 12, and 4 of 11 rats treated with AH.F5 did not develop diabetes when treatment was started at 2-3, 4, 5, and 6wks of age, respectively. The rats that did not develop diabetes were maintained for a minimum of 72 days to >150 days following the last dose of AH.F5. Eleven rats maintained for >150 days underwent an additional depletion and 5/11 developed diabetes within 8-19 days following start of depletion.Histological examination indicated that AH.F5 prevented and possibly reversed insulitis. Islets in about 50% of the treated rats remained free of inflammation following a second course of RT 6.1 T-cell depletion after the serum concentration of AH.F5 was negligible. In summary, CD40/154 blockade with AH.F5 prevents development of autoimmune diabetes if treatment is started prior to overt signs of beta cell destruction. The results indicate that the CD40/154 blockade can prevent diabetes by modifying the expansion or effector phase of the autoimmune diabetes.
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PMID:Prevention of autoimmune diabetes in the DRBB rat by CD40/154 blockade. 1241 84

The loss of self-tolerance leading to autoimmune type 1 diabetes in the NOD mouse model involves at least 19 genetic loci. In addition to their genetic defects in self-tolerance, NOD mice resist peripheral transplantation tolerance induced by costimulation blockade using donor-specific transfusion and anti-CD154 antibody. Hypothesizing that these two abnormalities might be related, we investigated whether they could be uncoupled through a genetic approach. Diabetes-resistant NOD and C57BL/6 stocks congenic for various reciprocally introduced Idd loci were assessed for their ability to be tolerized. Surprisingly, in NOD congenic mice that are almost completely protected from diabetes, costimulation blockade failed to prolong skin allograft survival. In reciprocal C57BL/6 congenic mice with NOD-derived Idd loci, skin allograft survival was readily prolonged by costimulation blockade. These data indicate that single or multiple combinations of evaluated Idd loci that dramatically reduce diabetes frequency do not correct resistance to peripheral transplantation tolerance induced by costimulation blockade. We suggest that mechanisms controlling autoimmunity and transplantation tolerance in NOD mice are not completely overlapping and are potentially distinct, or that the genetic threshold for normalizing the transplantation tolerance defect is higher than that for preventing autoimmune diabetes.
Diabetes 2003 Feb
PMID:NOD congenic mice genetically protected from autoimmune diabetes remain resistant to transplantation tolerance induction. 1254 Jun 3

Although the critical requirement of CD4 T cells in type I (insulin-dependent) diabetes mellitus (T1DM) has been well documented, information on the exact role(s) of CD4 T cells in T1DM development is still limited. Here, utilizing non-obese diabetic (NOD) mice deficient for CD154 (CD154-KO/NOD), we have identified a mandatory role of CD4 T cells as the functional source of CD154 in the initiation of T1DM. Without CD154, CD4 T cells were not capable of mediating help in disease development in NOD mice. In fact, full expression of CD154 on the CD4 T cells seems to be essential in the normal spontaneous development of T1DM, since no diabetes was observed in CD154(+/-) mice in which around half of CD4 T cells do not express CD154 at all, at least by the time they were 40 weeks old. It was also shown that transgenic expression of CD80 on beta cells of pancreatic islets, which is believed to provide beta cells with the ability to prime cytotoxic T lymphocytes specific for islet antigens, did not restore insulitis in CD154-KO/NOD mice. Taken collectively, these results indicated that CD4 T cells play a crucial role in T1DM as a source of CD154, and that the role of CD154 on CD4 T cells in insulitis may not be just to facilitate priming and expanding of auto-reactive CD8 T cells by activating antigen-presenting cells bearing islet antigens.
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PMID:A crucial role of CD4 T cells as a functional source of CD154 in the initiation of insulin-dependent diabetes mellitus in the non-obese diabetic mouse. 1261 79

Clinical islet transplantation is a successful procedure that can improve the quality of life in recipients with diabetes. A drawback of the procedure is the need for chronic administration of immunosuppressive drugs that, among other side effects, are potentially diabetogenic. Definition of immunosuppressive protocols that utilize nondiabetogenic compounds could further improve islet transplantation outcome. We used the NOD mouse to assess the effect of targeting the T-lymphocyte surface receptors CD45RB and CD154 in preventing loss of allogeneic islet grafts as a result of recurrence of autoimmunity and allorejection. Administration of the two antibodies led to significantly prolonged allograft survival, with a percentage of grafts surviving long-term. The therapeutic efficacy of the treatment was paralleled by a shift in CD45RB isoform expression on T-lymphocytes, increased in vitro responsiveness to interleukin-7, and increased in vitro gamma-interferon production after anti-CD3 antibody stimulation. Furthermore, graft infiltration by CD8+ T-cells was remarkably reduced. Recipient mice bearing functioning allografts were otherwise immunocompetent, as assessed in vivo and in vitro by numerous tests, including intragraft cytokine production, responsiveness to polyclonal stimulation and alloantigens, and analysis of cell subset phenotype. These data show that nondiabetogenic regimens of immunomodulation can lead to prolonged islet allograft survival in the challenging NOD mouse model.
Diabetes 2003 Apr
PMID:Prolonged islet allograft survival in diabetic NOD mice by targeting CD45RB and CD154. 1266 67

Once nonobese diabetic (NOD) mice become diabetic, they are highly resistant to islet transplantation. The precise mechanism of such resistance remains largely unknown. In the present study we tested the hypothesis that islet allograft survival in the diabetic NOD mouse is determined by the interplay of diverse islet-specific T cell subsets whose activation is regulated by CD28/CD154 costimulatory signals and the common gamma-chain (gammac; a shared signaling element by receptors for IL-2, IL-4, IL-7, IL-9, IL-15, and IL-21). We found that common gammac blockade is remarkably effective in blocking the onset and the ongoing autoimmune diabetes, whereas CD28/CD154 blockade has no effect in suppressing the ongoing diabetes. However, CD28/CD154 blockade completely blocks the alloimmune-mediated islet rejection. Also, a subset of memory-like T cells in the NOD mice is resistant to CD28/CD154 blockade, but is sensitive to the common gammac blockade. Nonetheless, neither common gammac blockade nor CD28/CD154 blockade can prevent islet allograft rejection in diabetic NOD mice. Treatment of diabetic NOD recipients with CD28/CD154 blockade plus gammac blockade markedly prolongs islet allograft survival compared with the controls. However, allograft tolerance is not achieved, and all CTLA-4Ig-, anti-CD154-, and anti-gammac-treated diabetic NOD mice eventually rejected the islet allografts. We concluded that the effector mechanisms in diabetic NOD hosts are inherently complex, and rejection in this model involves CD28/CD154/gammac-dependent and -independent mechanisms.
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PMID:Islet allograft rejection in nonobese diabetic mice involves the common gamma-chain and CD28/CD154-dependent and -independent mechanisms. 1450 Jun 90

CD4+CD25+ T cells regulate a variety of autoimmune and alloimmune responses including the development of autoimmune diabetes in non-obese diabetic (NOD) mice. We have examined the role of CD28/CTLA4/B7 interactions in the expansion and survival of CD4+CD25+ regulatory T cells (T(reg)) in this setting. CD28/ B7 interactions are essential in the development of T(reg) in the thymus and for their survival in the periphery. The CD28-mediated homeostasis of these cells is independent of Il2, OX40, CD40L, and survival factor Bcl-XI. In addition, analysis of T(reg) from CTLA4-deficient mice suggests that CTLA4 expression is not required for their development or function. However, non-activating anti-CTLA4 antibodies blocked the suppressor activity of regulatory cells in vitro. Thus, clinical application of co-stimulatory blockade using agents such as CTLA4Ig in the treatment of autoimmune disease may result in complicated outcomes.
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PMID:The role of CD28 and CTLA4 in the function and homeostasis of CD4+CD25+ regulatory T cells. 1460 12

Islet transplantation in children with autoimmune diabetes will require immunosuppression that has minimal toxicity and side-effects, and overcomes the barrier of autoimmunity. Since antibodies directed against the CD40/154 co-stimulatory pathway may meet these criteria, we have tested the ability of hamster antirat CD154 (AH.F5, Biogen) to prevent rejection of renal subcapsular islet allografts in streptozotocin (STZ) or autoimmune (AUTO) diabetic diabetes-resistant biobreeding (DRBB) rats. STZ diabetic rats that received anti-CD154 at 15 mg/kg per dose but not 10 mg/kg per dose did not have evidence of rejection until about 80-120 d post-transplantation, by which time antibody concentrations had returned to undetectable levels. Rats retreated with anti-CD154 before recurrence of diabetes had a prolonged period of disease-free survival. Most of these rats had recurrence following a spleen cell challenge. In contrast, AUTO diabetic DRBB rats treated with anti-CD154 had recurrence of diabetes between 7 and 12 d following transplantation of the Dark Agouti (DA) islets. In a separate set, AUTO diabetic rats that received a simultaneous islet isograft, islet allograft and thyroid allograft had focal accumulation of lymphocytes at the periphery of the isograft, while the islet and thyroid allografts had diffuse infiltration with lymphocytes and destruction of tissue with no residual staining for glucagon. Therefore, autoimmunity adds an additional barrier to islet allotransplantation that is not overcome with CD40/154 blockade in an animal model that closely parallels autoimmune diabetes in humans. The results indicate the importance of testing regimen of islet transplantation in animal models of autoimmune diabetes.
Pediatr Diabetes 2001 Dec
PMID:CD40/154 blockade and rejection of islet allografts in the streptozotocin and autoimmune diabetic rat. 1501 84


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