Diannexin decreases inflammatory cell infiltration into the islet graft, reduces β-cell apoptosis, and improves early graft function

Elaine Y. Cheng, Vijay K. Sharma, Christina Chang, Ruchuang Ding, Anthony C. Allison, David B. Leeser, Manikkam Suthanthiran, Hua Yang

Research output: Contribution to journalArticle

14 Citations (Scopus)

Abstract

Background.: A major unmet challenge is to reduce the islet mass needed for insulin independence in type 1 diabetic recipients after islet transplantation. The recombinant homodimer of human annexin V, diannexin, has completed a Phase II Clinical Trial in Kidney Transplantation (NCT00615966). Methods.: We developed a marginal islet mass transplantation model (10-12 islets per gram of recipient body weight) and investigated whether diannexin prevents β-cell apoptosis and improves islet graft function. Diannexin was administered to islet cell donors shortly before pancreas harvest, added to isolation reagents, and infused into recipients at the time of transplantation and repeated daily until day 4. Results.: In the syngeneic marginal islet mass transplantation model, the median time needed to achieve normoglycemia was reduced from 17.0 days among untreated controls to 3.5 days among diannexin-treated recipients (P=0.004). Histologic analysis of islet grafts harvested on day 3 posttransplantation revealed decreased macrophage (44.7%±9.8% vs. 19.2%±3.2%, P=0.007) and T-cell infiltration (25.9%±5.5% vs. 9.1%±1.1%, P=0.004), and a lower rate of islet cell apoptosis (20.5%±2.8% vs. 7.6%±2.3%, P=0.01) with diannexin treatment. Expression profiling of the islet grafts showed significantly lower levels of mRNA for the proapoptotic molecule Bid, but higher levels of interleukin-6, interferon-γ, and immunosuppressive cytokine interleukin-10. Conclusions.: Our findings demonstrate that diannexin improves the early function of marginal mass islet grafts, and its effects are associated with reductions in inflammatory cell infiltration and β-cell death by apoptosis after islet transplantation.

Original languageEnglish
Pages (from-to)709-716
Number of pages8
JournalTransplantation
Volume90
Issue number7
DOIs
Publication statusPublished - 15 Oct 2010
Externally publishedYes

Fingerprint

Islets of Langerhans Transplantation
Apoptosis
Transplants
Islets of Langerhans
Phase II Clinical Trials
Immunosuppressive Agents
Interleukin-10
Kidney Transplantation
Interferons
Pancreas
Interleukin-6
Cell Death
Transplantation
Macrophages
Body Weight
Insulin
Cytokines
T-Lymphocytes
Messenger RNA
Therapeutics

Keywords

  • Apoptosis/drug effects
  • Diabetes mellitus
  • Diannexin/therapeutic use
  • Experimental
  • Islet transplantation
  • Mice

ASJC Scopus subject areas

  • Transplantation

Cite this

Diannexin decreases inflammatory cell infiltration into the islet graft, reduces β-cell apoptosis, and improves early graft function. / Cheng, Elaine Y.; Sharma, Vijay K.; Chang, Christina; Ding, Ruchuang; Allison, Anthony C.; Leeser, David B.; Suthanthiran, Manikkam; Yang, Hua.

In: Transplantation, Vol. 90, No. 7, 15.10.2010, p. 709-716.

Research output: Contribution to journalArticle

Cheng, Elaine Y. ; Sharma, Vijay K. ; Chang, Christina ; Ding, Ruchuang ; Allison, Anthony C. ; Leeser, David B. ; Suthanthiran, Manikkam ; Yang, Hua. / Diannexin decreases inflammatory cell infiltration into the islet graft, reduces β-cell apoptosis, and improves early graft function. In: Transplantation. 2010 ; Vol. 90, No. 7. pp. 709-716.
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AU - Cheng, Elaine Y.

AU - Sharma, Vijay K.

AU - Chang, Christina

AU - Ding, Ruchuang

AU - Allison, Anthony C.

AU - Leeser, David B.

AU - Suthanthiran, Manikkam

AU - Yang, Hua

PY - 2010/10/15

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AB - Background.: A major unmet challenge is to reduce the islet mass needed for insulin independence in type 1 diabetic recipients after islet transplantation. The recombinant homodimer of human annexin V, diannexin, has completed a Phase II Clinical Trial in Kidney Transplantation (NCT00615966). Methods.: We developed a marginal islet mass transplantation model (10-12 islets per gram of recipient body weight) and investigated whether diannexin prevents β-cell apoptosis and improves islet graft function. Diannexin was administered to islet cell donors shortly before pancreas harvest, added to isolation reagents, and infused into recipients at the time of transplantation and repeated daily until day 4. Results.: In the syngeneic marginal islet mass transplantation model, the median time needed to achieve normoglycemia was reduced from 17.0 days among untreated controls to 3.5 days among diannexin-treated recipients (P=0.004). Histologic analysis of islet grafts harvested on day 3 posttransplantation revealed decreased macrophage (44.7%±9.8% vs. 19.2%±3.2%, P=0.007) and T-cell infiltration (25.9%±5.5% vs. 9.1%±1.1%, P=0.004), and a lower rate of islet cell apoptosis (20.5%±2.8% vs. 7.6%±2.3%, P=0.01) with diannexin treatment. Expression profiling of the islet grafts showed significantly lower levels of mRNA for the proapoptotic molecule Bid, but higher levels of interleukin-6, interferon-γ, and immunosuppressive cytokine interleukin-10. Conclusions.: Our findings demonstrate that diannexin improves the early function of marginal mass islet grafts, and its effects are associated with reductions in inflammatory cell infiltration and β-cell death by apoptosis after islet transplantation.

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