Donor Treatment With Carbon Monoxide Can Yield Islet Allograft Survival and Tolerance

• Published in: Diabetes (New York, N.Y.) Vol. 54; no. 5; pp. 1400 - 1406
• Main Authors: Wang, Hongjun, Lee, Soo Sun, Gao, Wenda, Czismadia, Eva, McDaid, James, Ollinger, Robert, Soares, Miguel P, Yamashita, Kenichiro, Bach, Fritz H
• Format: Journal Article
• Language: English
• Published: Alexandria, VA American Diabetes Association 01-05-2005
• Subjects: Animals; Antigens; Apoptosis; Biological and medical sciences; Carbon monoxide; Carbon Monoxide - pharmacology; Cobalt; Cytokines; Cytokines - analysis; Diabetes; Diabetes research; Diabetes. Impaired glucose tolerance; Endocrine pancreas. Apud cells (diseases); Endocrinopathies; Enzyme Induction; Etiopathogenesis. Screening. Investigations. Target tissue resistance; Glucose; Graft Survival - drug effects; Graft Survival - immunology; Heme Oxygenase (Decyclizing) - biosynthesis; Heme Oxygenase-1; Immune Tolerance; Islets of Langerhans Transplantation - immunology; Islets of Langerhans Transplantation - physiology; Male; Medical sciences; Membrane Proteins; Mice; Mice, Inbred DBA; Mice, Inbred Strains; Nitric oxide; Pancreatic beta cell transplantation; Pancreatic beta cells; Proteins; Time Factors; Transplantation; Transplantation, Homologous; Tumor necrosis factor-TNF; United States; Endocrinopathy; Treatment; Donor; Diabetes mellitus; Langerhans islet; Homograft; Tolerance; Yield; Carbon monoxide; Survival; Endocrine pancreas
• ISSN: 0012-1797; 1939-327X
• DOI: 10.2337/diabetes.54.5.1400

Donor Treatment With Carbon Monoxide Can Yield Islet Allograft Survival and Tolerance
Hongjun Wang 1 ,
Soo Sun Lee 1 ,
Wenda Gao 2 ,
Eva Czismadia 1 ,
James McDaid 1 ,
Robert Öllinger 1 ,
Miguel P. Soares 1 ,
Kenichiro Yamashita 1 and
Fritz H. Bach 1
1 Department of Surgery, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts
2 Department of Medicine, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts
Address correspondence and reprint requests to Hongjun Wang, Beth Israel Deaconess Medical Center, Harvard Medical School,
99 Brookline Ave., RN #361, Boston, MA 02215. E-mail: hwang3{at}bidmc.harvard.edu
Abstract
Treatment of animals or certain cells with carbon monoxide (CO), a product of heme degradation by heme oxygenase-1 (HO-1),
has potent anti-inflammatory and antiapoptotic effects that contribute to the survival of transplanted organs. We report here
that inducing HO-1 in, or administering CO to, only the donor can be used in a therapeutic manner to sustain the survival
of transplanted allogeneic islets. Similar treatments of only the islets or only the recipient are also salutary. Administering
CO only to the donor frequently leads to long-term survival of those islets in untreated allogeneic recipients, which are
then antigen-specifically tolerant. Several proinflammatory and proapoptotic genes that are strongly induced in islets after
transplantation in the untreated situation were significantly suppressed after administering CO to the donor without further
treatment. These included tumor necrosis factor-α, inducible nitric oxide synthase, monocyte chemoattractant protein-1, granzyme
B, and Fas/Fas ligand, all of which contribute to the pathogenesis of the rejection of transplanted islets. This correlated
with a lesser infiltration of recipient macrophages into the transplanted islets. Our present findings show that induction
of HO-1 in, or administration of CO to, only the donor, islets, or the recipient or combinations of such treatments improve
allogeneic islet survival.
CoPP, cobalt protoporphyrin-IX
HO-1, heme oxygenase-1
IL, interleukin
iNOS, inducible nitric oxide synthase
MCP-1, monocyte chemoattractant protein-1
MST, mean survival time
TNF-α, tumor necrosis factor-α
Footnotes
K.Y. and F.H.B. contributed equally to this work.
M.P.S. is currently affiliated with the Gulbenkian Institute of Science, Oeiras, Portugal.
Accepted January 28, 2005.
Received June 18, 2004.
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