Surgery Induces Human Mononuclear Cell Arginase I Expression

Bernard, Andrew C.; Shane, Matthew D.; Shirley, Lawrence A.; Maley, Mary E.; Boulanger, Bernard R.; Kearney, Paul A.; Ochoa, Juan B.

doi:10.1097/00005373-200109000-00012

Cited by 33 publications

(24 citation statements)

References 15 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…On an initially empiric basis, oral arginine supplementation was explored and found to show efficacy for improving immune function in patients suffering major trauma or undergoing extensive surgical procedures (28). It was subsequently confirmed that ArgI is transiently found at increased levels in these patients (29,30), supporting the clinical utility for dietary L-arginine supplementation in the reversal of immunosuppression. These clinical results encourage parallel translation to patients with cancer.…”

Section: Discussionmentioning

confidence: 68%

Neutrophil Degranulation and Immunosuppression in Patients with GBM: Restoration of Cellular Immune Function by Targeting Arginase I

Sippel

White

Nag³

et al. 2011

Clinical Cancer Research

170

151

View full text Add to dashboard Cite

Purpose: The source of glioblastoma (GBM)-associated immunosuppression remains multifactorial. We sought to clarify and therapeutically target myeloid cell-derived peripheral immunosuppression in patients with GBM.Experimental Design: Direct ex vivo T-cell function, serum Arginase I (ArgI) levels, and circulating myeloid lineage populations were compared between patients with GBM and normal donors or patients with other intracranial tumors. Immunofunctional assays were conducted using bulk and sorted cell populations to explore the potential transfer of myeloid cell-mediated immunosuppression and to identify a potential mechanism for these effects. ArgI-mediated immunosuppression was therapeutically targeted in vitro through pharmacologic inhibition or arginine supplementation.Results: We identified a significantly expanded population of circulating, degranulated neutrophils associated with elevated levels of serum ArgI and decreased T-cell CD3z expression within peripheral blood from patients with GBM. Sorted CD11b þ cells from patients with GBM were found to markedly suppress normal donor T-cell function in coculture, and media harvested from mitogen-stimulated GBM peripheral blood mononuclear cell (PBMC) or GBM-associated mixed lymphoid reactions showed ArgI levels that were significantly higher than controls. Critically, T-cell suppression in both settings could be completely reversed through pharmacologic ArgI inhibition or with arginine supplementation. Conclusions: These data indicate that peripheral cellular immunosuppression in patients with GBM is associated with neutrophil degranulation and elevated levels of circulating ArgI, and that T-cell function can be restored in these individuals by targeting ArgI. These data identify a novel pathway of GBM-mediated suppression of cellular immunity and offer a potential therapeutic window for improving antitumor immunity in affected patients. Clin Cancer Res; 17(22); 6992-7002. Ó2011 AACR.

show abstract

Section: Discussionmentioning

confidence: 68%

Neutrophil Degranulation and Immunosuppression in Patients with GBM: Restoration of Cellular Immune Function by Targeting Arginase I

Sippel

White

Nag³

et al. 2011

Clinical Cancer Research

170

151

View full text Add to dashboard Cite

show abstract

“…73,106 We have made nearly identical observations in humans after surgery and in mouse models of surgical trauma (data not shown). 74,100,101 Therefore, a wealth of data supports the hypothesis that arginine deficiency developed through increased ASE I expression may be modulating nitric oxide production in vivo. Peritoneal mouse macrophages (2ϫ10 6 cells/mL) were placed in culture.…”

Section: Arginine In Myeloid Cellsmentioning

confidence: 88%

“…100 Shortly thereafter, we demonstrated dramatic increases in ASE I expression in peripheral mononuclear cells in severely traumatized victims and also in patients undergoing elective surgery, demonstrating that alterations in arginine metabolism in the immune system are evolutionarily conserved across species. 74,101 ASE I exhibits 2 important biologic functions. The first is that it generates ornithine and urea from its substrate arginine.…”

Section: Arginine In Myeloid Cellsmentioning

confidence: 99%

A Rational Use of Immune Enhancing Diets: When Should We Use Dietary Arginine Supplementation?

2004

Self Cite

View full text Add to dashboard Cite

Controversies in any arena of human activity often result in the polarization of the individuals involved into 2 opposing camps. Controversy about the use of immune-enhancing diets (IEDs) is no exception. On one hand, some groups are proposing indiscriminate use of IEDs, whereas others have created guidelines advocating that their use should be banned for the critically ill. At stake is an emerging paradigm: that dietary manipulation of the immune system is possible and may become an important adjunct to other therapies, thus helping prevent or treat multiple diseases for millions worldwide. Under these circumstances, extremist claims of miraculous benefits or inappropriate assertions of evil can only delay the emergence of a nascent science. This paper is therefore a plea for moderation from both camps, lest we cause irreparable damage to our clinical practices and potential injury to individual patients. IEDs all contain arginine. However, they also contain other substances such as omega-3 fatty acids, and nucleotides. The use of all these nutrients together into commercial IEDs without adequate evaluation of their individual effects has prevented the development of mechanistic hypotheses of action. Despite this, IEDs have been tested extensively, allowing the development of guidelines for their use. IEDs should be used for surgical patients, especially those undergoing elective surgery. IEDs show no benefit and indeed can potentially harm patients with sepsis, especially in the nonsurgical group, and should not be used outside of research protocols. Advances in basic research have helped us understand mechanisms of how arginine contained in IEDs may help surgical patients but may be deleterious in patients with sepsis. A review of the basic mechanisms of action of arginine on the immune system is enclosed in this paper and should serve as a basis for the development of scientific principles that guide clinical use of IEDs.

show abstract

“…However, the normalization of arginase activity occurred in lower percentage of patients (57% in CRC, 42% in CRCLM) than that of L-arginine (about 70% in both groups). Because trauma increases arginase activity and surgery induces arginase expression [28,29], the reason of such discrepancy may be the surgical procedure itself.…”

Section: Discussionmentioning

confidence: 99%

l-Arginine as a factor increasing arginase significance in diagnosis of primary and metastatic colorectal cancer

Graboń

Mielczarek-Puta

Chrzanowska

et al. 2009

Clinical Biochemistry

View full text Add to dashboard Cite

Surgery Induces Human Mononuclear Cell Arginase I Expression

Abstract: Increased MNC arginase expression may contribute to postsurgical immune dysfunction by affecting arginine use and availability and nitric oxide metabolism in the immune system. Plasma IL-10 may play a role in regulating MNC arginase activity.

Cited by 33 publications

References 15 publications

Neutrophil Degranulation and Immunosuppression in Patients with GBM: Restoration of Cellular Immune Function by Targeting Arginase I

Neutrophil Degranulation and Immunosuppression in Patients with GBM: Restoration of Cellular Immune Function by Targeting Arginase I

A Rational Use of Immune Enhancing Diets: When Should We Use Dietary Arginine Supplementation?

l-Arginine as a factor increasing arginase significance in diagnosis of primary and metastatic colorectal cancer

Contact Info

Product

Resources

About