Human Pancreatic Islets Produce and Secrete MCP-1/CCL2: Relevance in Human Islet Transplantation

Piemonti, Lorenzo; Leone, Biagio Eugenio; Nano, Rita; Saccani, Alessandra; Monti, Paolo; Maffi, Paola; Bianchi, Giancarlo; Sica, Antonio; Peri, Giuseppe; Melzi, Raffaella; Aldrighetti, Luca; Secchi, Antonio; Allavena, Paola; Bertuzzi, Federico

doi:10.2337/diabetes.51.1.55

Cited by 276 publications

(259 citation statements)

References 69 publications

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“…MCP-1 mRNA expression was also shown to be up-regulated in rat renal isografts [70] and the chemokine probably plays a role in the attraction of mononuclear cells to the graft. In line with this possibility, high basal MCP-1 production by human islets correlates with a poor clinical outcome following islet transplantation in patients with Type 1 diabetes [71].…”

Section: Discussionmentioning

confidence: 66%

IL-1β and IFN-γ induce the expression of diverse chemokines and IL-15 in human and rat pancreatic islet cells, and in islets from pre-diabetic NOD mice

et al. 2003

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Aims/hypothesis. Cytokines and chemokines are important mediators of immune responses due to their ability to recruit and activate leukocytes. Using microarray analysis we observed that rat beta cells exposed to IL-1β and IFN-γ have increased mRNA levels of chemokines and IL-15. The aim of this study was to characterize the expression of IP-10, MIP-3α, fractalkine and IL-15 in rat beta cells, human pancreatic islets, and in islets isolated from NOD mice, both during the pre-diabetic period and following islet transplantation. Methods. FACS-purified rat beta cells and human islets were cultured with IL-1β, IFN-γ and/or TNF-α. Islets were isolated from NOD or BALB/c mice at different ages. For syngeneic islet transplantation, 2-or 3-week-old NOD islets were grafted under the kidney capsule of spontaneously diabetic NOD recipients. Chemokine and IL-15 mRNA expression and protein release were evaluated, respectively, by RT-PCR and ELISA.Results. Human islets and rat beta cells express IP-10, MIP-3α, fractalkine and IL-15 mRNAs upon exposure to cytokines. The expression of IL-15, IP-10 and fractalkine is regulated by IFN-γ, while the expression of MIP-3α is IL-1β-dependent. Moreover, cytokines induced IL-15, IP-10, Mig, I-TAC and MIP-3α protein accumulation in culture medium from human islets. In vivo, there was an age-related increase in IL-15, IP-10 and MIP-3α expression in islets isolated from NOD mice. Following syngeneic islet transplantation, increased expression of IL-1β, IFN-γ, fractalkine, IP-10, MCP-1 and MIP-3α mRNAs were observed in the grafts. Conclusion/interpretation. Cytokine-exposed islets or beta cells express chemokines and IL-15. This could contribute to the recruitment and activation of mononuclear cells and development of insulitis in early Type 1 diabetes and during graft destruction. [Diabetologia (2003) 46:255-266] Keywords Type 1 diabetes mellitus, chemokines, IL-15, NOD mice, beta cells, interferon-γ, interleukin-1β, pancreatic islets, islet transplantation, insulitis.

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Section: Discussionmentioning

confidence: 66%

IL-1β and IFN-γ induce the expression of diverse chemokines and IL-15 in human and rat pancreatic islet cells, and in islets from pre-diabetic NOD mice

et al. 2003

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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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“…It is important to note that because the time frame of graft dysfunction occurred very early after transplantation, it is unlikely that adaptive immunity contributed to graft failure, but rather that innate immunity was responsible for interfering with early engraftment and function. In human islet transplant recipients, high MCP-1 expression in islet grafts is associated with decreased long-term graft survival (11). In an autoimmune model in mice, chemokines produced by islets contributed to insulitis and immune-mediated destruction of the islets (31).…”

Section: Discussionmentioning

confidence: 99%

“…These mediators include chemokines, which promote chemotaxis, proliferation, and differentiation of additional leukocytes, and therefore play important roles in amplifying immunity. It is clear that many parenchymal cell types can also respond to pathogens and release similar sets of chemokines (10)(11)(12). In addition, chemokine function is necessary to translate innate into adaptive immune responses (13).…”

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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Human Pancreatic Islets Produce and Secrete MCP-1/CCL2: Relevance in Human Islet Transplantation

Cited by 276 publications

References 69 publications

IL-1β and IFN-γ induce the expression of diverse chemokines and IL-15 in human and rat pancreatic islet cells, and in islets from pre-diabetic NOD mice

IL-1β and IFN-γ induce the expression of diverse chemokines and IL-15 in human and rat pancreatic islet cells, and in islets from pre-diabetic NOD mice

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

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

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