Primary nonfunction of islet xenografts in rat recipients results from non-t-cell-mediated immune responses

Deng, Shaoping; Ketchum, R.J.; Kucher, T.; Weber, Markus; Naji, Ali; Brayman, Kenneth L.

doi:10.1016/s0041-1345(97)00032-8

Cited by 11 publications

(8 citation statements)

References 1 publication

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“…One cause limiting the success of experimental xenotransplantation-early graft failure, a tendency of islet grafts to fail to function after a technically perfect transplantation-has been subject of many investigations. According to recent reports, the underlying basis for this inability to function and maintain normoglycemia after islet grafting is the action of local inflammatory agents (6,12,13). However, the exact triggers of this phenomenon remain unknown.…”

Section: Discussionmentioning

confidence: 99%

“…Although the exact mechanisms involved in this early graft failure are still unexplained, several investigators have suggested a role for inflammatory processes mediated by macrophages (12,13). Indeed, macrophages are the first cells to infiltrate the pancreatic islets, even before T-cells, and they can secrete proinflammatory cytokines, which allow for the recruitment and activation of other invasive immune cells.…”

Section: Ca Gysemans and Associatesmentioning

confidence: 99%

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Early graft failure of xenogeneic islets in NOD mice is accompanied by high levels of interleukin-1 and low levels of transforming growth factor-beta mRNA in the grafts.

Gysemans¹,

Waer²,

Valckx³

et al. 2000

Diabetes

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Early graft failure, graft rejection, and autoimmune recurrence remain unresolved issues in islet xenotransplantation in type 1 diabetes. The first aim of this study was to examine the existence of early graft failure in spontaneously diabetic autoimmune NOD mice after rat islet transplantation under technically controlled circumstances. The second aim was to examine the mediators of this early xenograft dysfunction. First, we demonstrated a higher percentage of early xenograft failure (48%) in spontaneously diabetic NOD mice as compared with chemically diabetic old NOD (13%, P < 0.05) and C57Bl/6 (7%, P < 0.01) mice. In addition, in spontaneously diabetic NOD mice, xenogeneic islets displayed early graft failure more frequently than allogeneic (23%, P ≤ 0.05) or isogeneic islets (7%, P < 0.01). No early graft failure was observed in allotransplantation or isotransplantation in chemically diabetic mice. Reverse transcriptase-polymerase chain reaction analysis of cytokine mRNA in islet xenografts 8 h after transplantation showed higher levels of interleukin (IL)-1 mRNA in autoimmune diabetic mice compared with chemically diabetic old NOD mice (1.40 ± 0.32 vs. 0.90 ± 0.14 IL-1 copies/␤-actin copies, P < 0.05). In contrast, mRNA levels of transforming growth factor (TGF)-␤ were lower in spontaneously diabetic NOD mice than in chemically diabetic old NOD mice (0.67 ± 0.16 vs. 1.36 ± 0.50 TGF-␤ copies/␤-actin copies, P < 0.05). No differences in tumor necrosis factor-␣, IL-6, and inducible nitric oxide synthase were seen between autoimmune and nonautoimmune diabetic mice. T-cell cytokines (IL-2, IL-4, IL-10, and ␥-interferon) were absent in all mice until 48 h after transplantation. These data suggest that early islet xenograft failure is more common in spontaneously diabetic NOD mice and could be due to a nonspecific inflammatory reaction locally in the grafts.

show abstract

Section: Discussionmentioning

confidence: 99%

Section: Ca Gysemans and Associatesmentioning

confidence: 99%

Early graft failure of xenogeneic islets in NOD mice is accompanied by high levels of interleukin-1 and low levels of transforming growth factor-beta mRNA in the grafts.

Gysemans¹,

Waer²,

Valckx³

et al. 2000

Diabetes

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“…PNF may be the consequence of poor functional quality of the grafted tissue, an inadequate mass of transplanted islets, or lack of vascularization of the graft. However, substantial evidence now suggests that exposure to an early, nonimmune inflammatory injury is largely responsible for the observed destruction of islets and may well amplify subsequent immune reactions (2–6).…”

Section: Introductionmentioning

confidence: 99%

Thrombomodulin Improves Early Outcomes After Intraportal Islet Transplantation

Cui

Wilson

Wen

et al. 2009

American Journal of Transplantation

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Primary islet nonfunction due to an instant blood mediated inflammatory reaction (IBMIR) leads to an increase in donor islet mass required to achieve euglycemia. In the presence of thrombin, thrombomodulin generates activated protein C (APC), which limits procoagulant and proinflammatory responses. In this study, we postulated that liposomal formulations of thrombomodulin (lipo-TM), due to its propensity for preferential uptake in the liver, would enhance intraportal engraftment of allogeneic islets by inhibiting the IBMIR. Diabetic C57BL/6J mice underwent intraportal transplantation with B10.BR murine islets. In the absence of treatment, conversion to euglycemia was observed among 29% of mice receiving 250 allo-islets. In contrast, a single infusion of lipo-TM led to euglycemia in 83% of recipients (p = 0.0019). Fibrin deposition (p < 0.0001), neutrophil infiltration (p < 0.0001), as well as expression TNF-a and IL-b (p < 0.03) were significantly reduced. Significantly, thrombotic responses mediated by human islets in contact with human blood were also reduced by this approach. Lipo-TM improves the engraftment of allogeneic islets through a reduction in local thrombotic and inflammatory processes. As an enzyme-based pharmacotherapeutic, this strategy offers the potential for local generation of APC at the site of islet infusion, during the initial period of elevated thrombin production.

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“…However, the function and survival of transplanted islets are limited by well-described inflammatory responses that resemble innate immunity (14)(15)(16)(17). Hence, innate immunity to adenoviral vectors may further augment inflammation and impair islet function and survival.…”

Section: Introductionmentioning

confidence: 99%

Adenovirus Transduction Induces Expression of Multiple Chemokines and Chemokine Receptors in Murine β Cells and Pancreatic Islets

Zhang

Schröppel

Chen

et al. 2003

American Journal of Transplantation

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Primary nonfunction of islet xenografts in rat recipients results from non-t-cell-mediated immune responses

Cited by 11 publications

References 1 publication

Early graft failure of xenogeneic islets in NOD mice is accompanied by high levels of interleukin-1 and low levels of transforming growth factor-beta mRNA in the grafts.

Early graft failure of xenogeneic islets in NOD mice is accompanied by high levels of interleukin-1 and low levels of transforming growth factor-beta mRNA in the grafts.

Thrombomodulin Improves Early Outcomes After Intraportal Islet Transplantation

Adenovirus Transduction Induces Expression of Multiple Chemokines and Chemokine Receptors in Murine β Cells and Pancreatic Islets

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