Autoantibody Response to Islet Transplantation in Type 1 Diabetes

Bosi, Emanuele; Braghi, S.; Maffi, Paola; Scirpoli, Miriam; Bertuzzi, Federico; Pozza, G.; Secchi, Antonio; Bonifacio, Ezio

doi:10.2337/diabetes.50.11.2464

Cited by 118 publications

(70 citation statements)

References 38 publications

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“…Other factors such as the inflammatory reaction during engraftment [21], the metabolic condition [22] or the allo-and auto-response of recipients [23,24] have also been shown to influence in vivo function of transplanted islets. Islet quality may, therefore, represent another prerequisite for successful transplantation.…”

Section: Discussionmentioning

confidence: 99%

Islet isolation for allotransplantation: variables associated with successful islet yield and graft function

et al. 2005

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Aims/hypothesis: Efficient islet isolation is an important prerequisite for successful clinical islet transplantation. Although progressively improved, islet yield and quality are, however, unpredictable and variable and require standardisation. Methods: Since 1989 we have processed 437 pancreases using the automated method. The donor characteristics, pancreas procurement, and digestion and purification procedures including a wide enzyme characterisation of these pancreases were analysed and correlated with islet yield and transplant outcome. Results: By univariate analysis, islet yield was significantly associated with donor age (r=0.16; p=0.0009), BMI (r=0.19; p= 0.0004), good pancreas condition (p=0.0031) and weight (r=0.15; p=0.0056), total collagenase activity (r=0.22; p= 0.0001), adjusted collagenase activity/mg (r=0.18; p=0.0002), collagenase activity/solution volume (r=0.18; p=0.0002) and neutral protease activity/solution volume (r=0.14; p= 0.0029). A statistically significant contribution to the variability of islet yield in a multivariate analysis performed on donor variables was found for donor BMI (p=0.0008). In a multivariate analysis performed on pancreas variables a contribution was found for pancreas weight (p=0.0064), and for a multivariate analysis performed on digestion variables we found a contribution for digestion time (p= 0.0048) and total collagenase activity (p=0.0001). Twenty-four patients with type 1 diabetes received single islet preparations from single donors. In these patients, multivariate analyses showed that the reduction in insulin requirement was significantly associated with morphological aspects of islets (p= 0.0010) and that 1-month C-peptide values were associated with islet purity (p=0.0071). Conclusions/interpretation: These data provide baseline donor, digestion and purification selection criteria for islet isolation using the automated method and indicate that the morphological aspect may be a clinically relevant measure of islets on which the decision for transplant can be based.

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Section: Discussionmentioning

confidence: 99%

Islet isolation for allotransplantation: variables associated with successful islet yield and graft function

et al. 2005

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“…Diabetes onset occurred 10 days following cell transfer. Grafts were harvested 1 day following diabetes onset, and from a grafted NOD.scid mouse (e and f) that received 5 ϫ 10 6 SCs from a spontaneously diabetic NOD mouse. Diabetes onset occurred 15 days postcell transfer.…”

Section: Discussionmentioning

confidence: 99%

“…Because islet autoreactive T cells should be restricted to a complex of isletassociated Ag presented in self-MHC, it has been suggested that transplanting allografts bearing a poor MHC match between the donor and the recipient might reduce the risk of recurrent autoimmune diabetes following transplantation (2). Unfortunately, clinical studies have indicated that pancreatic allografts are also susceptible to autoimmune disease recurrence (3)(4)(5)(6). Taken together these studies have established the following important points.…”

mentioning

confidence: 94%

MHC-Mismatched Islet Allografts Are Vulnerable to Autoimmune Recognition In Vivo

Kupfer

Crawford

Pham

et al. 2005

The Journal of Immunology

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When transplanted into type 1a diabetic recipients, islet allografts are subject both to conventional allograft immunity and, presumably, to recurrent autoimmune (islet-specific) pathogenesis. Importantly, CD4 T cells play a central role both in islet allograft rejection and in autoimmune disease recurrence leading to the destruction of syngeneic islet transplants in diabetic NOD mice. However, it is unclear how NOD host MHC class II (I-Ag7)-restricted, autoreactive CD4 T cells may also contribute to the recognition of allogeneic islet grafts that express disparate MHC class II molecules. We hypothesized that islet-specific CD4 T cells can target MHC-mismatched islet allografts for destruction via the “indirect” (host APC-dependent) pathway of Ag recognition. To test this hypothesis, we determined whether NOD-derived, islet-specific CD4 T cells (BDC-2.5 TCR transgenic cells) could damage MHC-mismatched islets in vivo independent of conventional allograft immunity. Results demonstrate that BDC-2.5 CD4 T cells can vigorously destroy MHC class II-disparate islet allografts established in NOD.scid recipients. Tissue injury is tissue-specific in that BDC-2.5 T cells destroy donor-type islet, but not thyroid allografts established in the same NOD.scid recipient. Furthermore, BDC-2.5 CD4 T cells acutely destroy MHC class II-deficient islet allografts in vivo, indicating that autoimmune pathogenesis can be completely independent of donor MHC class II expression. Taken together, these findings indicate that MHC-mismatched islet allografts can be vulnerable to autoimmune pathogenesis triggered by autoreactive CD4 T cells, presumably through indirect autoantigen recognition in vivo.

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“…Similarly, the results of islet transplantation in Type 1 diabetic patients were very disappointing for many years, but studies to determine whether auto-and alloreactivity were dealt with sufficiently in these situations were lacking. Careful and extensive immunological studies have now provided compelling evidence that the fate of the islet allograft is determined by effective immunotherapy directed against T-cells [10,102]. Such studies will improve the success of clinical islet transplantation in the future by improved immunotherapy [103].…”

Section: Immunotherapymentioning

confidence: 99%