NK cells, macrophages, and humoral immune responses are dominant in primary nonfunction of islet grafts in the dog-to-rat xenotransplant model

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

doi:10.1016/s0041-1345(97)00232-7

Cited by 12 publications

(8 citation statements)

References 3 publications

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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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“…Further, instant blood-mediated inflammatory reactions negatively influence islet engraftment and survival (14, 15). These inflammatory reactions together elicit strong adaptive immune response characterized primarily by macrophage-mediated islet destruction (16-18). In addition, β-cells are extremely sensitive to proinflammatory cytokines such as IL-1, IFN-γ and TNF-α, which also inhibits glucose-stimulated insulin secretion and promote islet degeneration (16-18).…”

Section: Introductionmentioning

confidence: 99%

“…These inflammatory reactions together elicit strong adaptive immune response characterized primarily by macrophage-mediated islet destruction (16-18). In addition, β-cells are extremely sensitive to proinflammatory cytokines such as IL-1, IFN-γ and TNF-α, which also inhibits glucose-stimulated insulin secretion and promote islet degeneration (16-18). As is the case for other organ transplantation, islet grafts are also subjected to rejection.…”

Section: Introductionmentioning

confidence: 99%

Oleanolic Acid, a Plant Triterpenoid, Significantly Improves Survival and Function of Islet Allograft

et al. 2009

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Background Oleanolic acid (OA) is a ubiquitous triterpenoid, with potent anti-oxidant and anti-inflammatory properties. Here we tested if these combined properties of OA can prevent non-immunologic primary nonfunctioning and immunologic phenomena ascribed to graft rejection hence prolong islet allograft survival. Methods Islet transplants were performed under kidney capsule of STZ induced diabetic C57BL/6 mice with BALB/c islets. Recipients were treated with 0.5mg/day of OA i.p. serum samples were collected once in two days and used for luminex, ELISA and donor specific antibody screening. Transplanted mice were sacrificed at different time intervals to obtain splenocytes and kidney samples for ELISPOT, MLR and immunohistochemical studies respectively. Results Post-transplant the decrement of blood glucose was significantly faster in mice receiving OA <2±1days compared to untreated (4±2). OA prolonged survival of transplanted islets up to 23±3 days, and reversed diabetes even with 250 islets. Treatment group showed increased serum IL-10(2fold) and decreased IP-10 and IL-4(3) in luminex. Significantly reduced frequency of IFNγ(4.5fold) IL-4(3.5), IL-2(2.3) and IL-17(4) producing T cell populations were found in ELISPOT. OA treated grafts had significant reduced and delayed infiltration of CD4+ and CD8+ T cells. OA also delayed donor specific antibody generation up to 19 days following transplantation. Combined treatment with CSA, OA further prolonged the islet allograft survival to 34 ± 3 days. Conclusions In conclusion OA is an attractive, dietary non-toxic plant triterpenoid, which suppresses the production of pro-inflammatory cytokines and delays graft specific immune responses to prolong islet allograft survival.

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“…For example, human NK cells can be activated by porcine endothelial cells [6]. Also, NK cells comprise a dramatic early component in dog-to-rat islet xenografts [7]. However, as noted above, lymphocyte-deficient mouse models that are NK-cell replete fail to reject islet xenografts.…”

Section: Innate Immunitymentioning

confidence: 99%

Pancreatic islet xenotransplantation: Barriers and prospects

Rayat

Gill

2003

Curr Diab Rep

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Dramatic clinical advances indicate that pancreatic islet transplants can reliably restore euglycemia in insulin-dependent patients. However, clinical success actually highlights the pronounced deficiency of allogeneic pancreata available for islet isolation. This pressing issue has revitalized ongoing efforts to develop surrogate donor sources. Xenogeneic donors form a potential alternative tissue source because they can be generated in large numbers and are amenable to genetic engineering. However, there is less understanding of the innate and adaptive immune barriers to islet xenografts relative to those encountered by allografts. Presented evidence indicates that both innate and antigen-specific adaptive immune responses significantly contribute to islet xenograft rejection. Recent evidence suggests that the capacity to induce tolerance to islet xenografts may not differ markedly from strategies used to induce allograft tolerance.

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NK cells, macrophages, and humoral immune responses are dominant in primary nonfunction of islet grafts in the dog-to-rat xenotransplant model

Cited by 12 publications

References 3 publications

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.

Oleanolic Acid, a Plant Triterpenoid, Significantly Improves Survival and Function of Islet Allograft

Pancreatic islet xenotransplantation: Barriers and prospects

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