Importance of hyperglycemia on the primary function of allogeneic islet transplants1

Makhlouf, L.; Duvivier‐Kali, Valérie F.; Bonner-Weir, Susan; Dieperink, Hans; Weir, Gordon C.; Sayegh, Mohamed H.

doi:10.1097/01.tp.0000080881.75767.0e

Cited by 37 publications

(27 citation statements)

References 35 publications

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“…Thus, the GVA effect is probably minimal in TBI-conditioned recipients given TCD-BM. Second, residual host-type T cells cannot recognize donor-type alloantigen in the MHC-mismatched NOD chimeras in the absence of host-type DCs, because NOD mice were reported to have potent indirect CD4 + T cell response to alloantigens (52). We have observed that in the MHC-mismatched mixed chimeric NOD recipients, the presence of similar percentage of host-type CD4 + T cells did not mediate any rejection either.…”

Section: Discussionmentioning

confidence: 72%

MHC-Mismatched Chimerism Is Required for Induction of Transplantation Tolerance in Autoimmune Nonobese Diabetic Recipients

Wang

Racine

Zhang

et al. 2014

The Journal of Immunology

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In nonautoimmune recipients, induction of mixed and complete chimerism with hematopoietic progenitor cells from MHC (HLA)-matched or -mismatched donors are effective approaches for induction of organ transplantation immune tolerance in both animal models and patients. But it is still unclear whether this is the case in autoimmune recipients. With the autoimmune diabetic NOD mouse model, we report that, although mixed and complete MHC-mismatched chimerism provide immune tolerance to donor-type islet and skin transplants, neither mixed nor complete MHC-matched chimerism does. The MHC-mismatched chimerism not only tolerizes the de novo developed, but also the residual pre-existing host-type T cells in a mismatched MHC class II–dependent manner. In the MHC-mismatched chimeras, the residual host-type peripheral T cells appear to be anergic with upregulation of PD-1 and downregulation of IL-7Rα. Conversely, in the MHC-matched chimeras, the residual host-type peripheral T cells manifest both alloreactivity and autoreactivity; they not only mediate insulitis and sialitis in the recipient, but also reject allogeneic donor-type islet and skin grafts. Interestingly, transgenic autoreactive BDC2.5 T cells from Rag1+/+, but not from Rag1−/−, NOD mice show alloreactivity and mediate both insulitis and rejection of allografts. Taken together, MHC-mismatched, but not MHC-matched, chimerism can effectively provide transplantation immune tolerance in autoimmune recipients.

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Section: Discussionmentioning

confidence: 72%

MHC-Mismatched Chimerism Is Required for Induction of Transplantation Tolerance in Autoimmune Nonobese Diabetic Recipients

Wang

Racine

Zhang

et al. 2014

The Journal of Immunology

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“…For example, in vitro co-culture experiments have shown that MSCs increase islet viability by upregulating anti-apoptotic genes and improve insulin secretory function by modulating islet ATP content [27]. These effects are likely to be important in the immediate post-transplantation period when improved glycaemic control will favour effective islet engraftment by maintaining function [6,28] and enhancing revascularisation [29]. These factors alone are unlikely to account for the beneficial effects of MSCs in our experiments.…”

Section: Discussionmentioning

confidence: 83%

Co-transplantation of mesenchymal stem cells maintains islet organisation and morphology in mice

et al. 2011

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Aims/hypothesis Recent studies have shown that mesenchymal stem cells (MSCs) secrete several factors that improve survival and function of transplanted islets. Implantation of islets beneath the kidney capsule results in morphological changes, due to interactions of the graft with the host, thus impairing islet function. We co-transplanted MSCs with islets to determine their effects on the remodelling process and studied graft function in a mouse model of minimal islet mass. Methods Islets were syngeneically transplanted, either alone or with kidney-derived MSCs, underneath the kidney capsule of streptozotocin-induced diabetic C57Bl/6 mice. Blood glucose levels were monitored and intraperitoneal glucose tolerance tests carried out. Hormone contents of grafts and pancreas were assessed by radioimmunoassay. Graft morphology and vascularisation were evaluated by immunohistochemistry. Results MSCs improved the capacity of islet grafts to reverse hyperglycaemia, with 92% of mice co-transplanted with MSCs reverting to normoglycaemia, compared with 42% of those transplanted with islets alone. Average blood glucose concentrations were lower throughout the 1 month monitoring period in MSC co-transplanted mice. MSCs did not alter graft hormone content. Islets co-transplanted with MSCs maintained a morphology that more closely resembled that of islets in the endogenous pancreas, both in terms of size, and of endocrine and endothelial cell distribution. Vascular engraftment was superior in MSC co-transplanted mice, as shown by increased endothelial cell numbers within the endocrine tissue. Conclusions/interpretation Co-transplantation of islets with MSCs had a profound impact on the remodelling process, maintaining islet organisation and improving islet revascularisation. MSCs also improved the capacity of islets to reverse hyperglycaemia.

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“…A normoglycaemic environment, in contrast to hyperglycaemia, provides better islet transplantation results [14,17,18] for uncertain reasons that may include enhanced beta cell growth of the grafts [19], and/or avoidance of hyperglycaemia-induced increased oxygen demand with resulting hypoxia, a pro-apoptotic state of beta cells, and less-efficient vascularisation [20,21], although it seems that in the long term, vascular density is unchanged by hyperglycaemia [22]. It cannot be ruled out that nephrectomy leads to release of compensatory growth factors in the contralateral kidney where the 75-islet graft is situated, thus stimulating islet growth [23]; even so, a remarkably low number of islets was required to maintain normoglycaemia.…”

Section: Discussionmentioning

confidence: 99%

Islet transplantation outcomes in mice are better with fresh islets and exendin-4 treatment

King

Lock

et al. 2005

Diabetologia

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Aims/hypothesis: Although islet transplantation in diabetes holds great promise, two or three donor pancreases are usually required to achieve normoglycaemia in human or rodent recipients. We investigated whether there were differences between fresh and cultured islets in terms of transplantation outcome. We also investigated the effects of normoglycaemia during engraftment and the effects of exendin-4, a glucagon-like peptide-1 receptor agonist, on islet transplantation. Materials and methods: Seventy-five fresh islets were transplanted to the right kidney of diabetic mice and 425 fresh islets were transplanted to the left kidney. The mice were treated with exendin-4 or vehicle for 14 days, after which the large graft was removed by left nephrectomy. In a separate set of experiments, islets cultured in the presence or absence of exendin-4 for 72 h, or fresh islets, were transplanted to diabetic mice. In both sets of experiments, blood glucose levels were monitored. Results: Compared with cultured islets, fresh islets were more effective at reversing hyperglycaemia in mice. The treatment of the recipient mice with exendin-4 did not have beneficial effects on glucose homeostasis. However, when islets are cultured, exendin-4 treatment increases the rate of reversal of hyperglycaemia, but not to the degree of fresh islets. Conclusions/ interpretation: Fresh islets are more effective than cultured islets at reversing hyperglycaemia. Exendin-4 has beneficial effects on islet transplantation.

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Importance of hyperglycemia on the primary function of allogeneic islet transplants1

Abstract: This study demonstrates that severe hyperglycemia impairs islet allograft function in BALB/c and NOD mice and that successful islet allotransplantation depends on the degree of hyperglycemia in the recipient.

Cited by 37 publications

References 35 publications

MHC-Mismatched Chimerism Is Required for Induction of Transplantation Tolerance in Autoimmune Nonobese Diabetic Recipients

MHC-Mismatched Chimerism Is Required for Induction of Transplantation Tolerance in Autoimmune Nonobese Diabetic Recipients

Co-transplantation of mesenchymal stem cells maintains islet organisation and morphology in mice

Islet transplantation outcomes in mice are better with fresh islets and exendin-4 treatment

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