High arginine levels in intravenous hyperalimentation abrogate post-traumatic immune suppression

Barbul, Adrian; Wasserkrug, Hannah L.; Yoshimura, N; Tao, Robert C.; Efron, Gershon

doi:10.1016/0022-4804(84)90149-5

Cited by 72 publications

(20 citation statements)

References 2 publications

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“…Arginase I metabolizes arginine to ornithine. Patients with severe trauma, who also have an increased arginase activity in PBMC, have a rapid decline in serum arginine levels (9,10). Mean plasma levels of arginine were significantly decreased in the 15 patients studied (28.48 F 32.51 Amol/L) compared with controls (90.0 F 15.56 Amol/L) (Fig.…”

Section: Mdsc In Patients With Metastatic Rccmentioning

confidence: 89%

Arginase, Prostaglandins, and Myeloid-Derived Suppressor Cells in Renal Cell Carcinoma

Ochoa

Zea

Hernandez

et al. 2007

Clinical Cancer Research

430

325

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Tumor-induced tolerance is a well-established phenomenon in cancer patients that can severely impair the therapeutic efficacy of immunotherapy. One mechanism leading to T-cell tolerance is the generation of myeloid-derived suppressor cells (MDSC) by soluble factors produced by the tumor. MDSC express CD11b + as a common marker but may vary in their stage of maturation, depending on the tumor factors being produced. Arginase production by MDSC depletes arginine from the tumor microenvironment and impairs T-cell signal transduction and function. We studied whether an increase in MDSC could explain the molecular alterations and dysfunction found in T cells of patients with renal cell carcinoma (RCC). Arginase activity in the peripheral blood mononuclear cells of 117 RCC patients was increased between 6-to 8-fold compared with normal controls. The increased arginase activity was limited to the CD11b + CD14 À myeloid cells and resulted in significantly decreased serum levels of arginine and increased ornithine in patients. Depletion of MDSC restored IFN-g production and T-cell proliferation. Preliminary data suggest that prostaglandin E 2 produced by the tumor induces arginase I expression in MDSC. Therefore, blocking MDSC activity may enhance the therapeutic efficacy of immunotherapy in RCC. Immunotherapy with cytokines, such as interleukin-2 (IL-2),has become a standard of care for patients with renal cell carcinoma (RCC). However, only 20% to 30% of patients have a partial or complete response (1), which is significantly lower than the therapeutic efficacy suggested by animal models. One possible explanation is that tumor-induced tolerance diminishes the potential therapeutic effect of T cells, the principal effector cells in most forms of immunotherapy. Over the last decade, several mechanisms by which tumors escape the immune response have been described. These can be divided into three major groups: alterations in antigen expression in tumor cells to make them less detectable, the active suppression of dendritic and T-cell function by inhibitory molecules or factors produced by tumors, and the induction of cells that can suppress the immune response, including myeloid-derived suppressor cells (MDSC) and regulatory T cells. We have focused our work on characterizing MDSC and the mechanisms by which they cause T-cell dysfunction in cancer.

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Section: Mdsc In Patients With Metastatic Rccmentioning

confidence: 89%

Arginase, Prostaglandins, and Myeloid-Derived Suppressor Cells in Renal Cell Carcinoma

Ochoa

Zea

Hernandez

et al. 2007

Clinical Cancer Research

430

325

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“…The infusion of high doses of L-arginine results in a recovery of T cell proliferation and an increase in the number of CD4 ϩ cells (15)(16)(17). However, the mechanisms by which low levels of L-arginine impair T cell function have remained unclear.…”

mentioning

confidence: 99%

l-Arginine Consumption by Macrophages Modulates the Expression of CD3ζ Chain in T Lymphocytes

Rodríguez

Zea

DeSalvo

et al. 2003

The Journal of Immunology

426

367

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l-Arginine plays a central role in the normal function of several organs including the immune system. It is metabolized in macrophages by inducible nitric oxide synthase to produce nitric oxide, important in the cytotoxic mechanisms, and by arginase I (ASE I) and arginase II (ASE II) to synthesize l-ornithine and urea, the first being the precursor for the production of polyamines needed for cell proliferation. l-Arginine availability can modulate T cell function. Human T cells stimulated and cultured in the absence of l-arginine lose the expression of the TCR ζ-chain (CD3ζ) and have an impaired proliferation and a decreased cytokine production. The aim of this work was to test whether activated macrophages could modulate extracellular levels of l-arginine and alter T cell function, and to determine which metabolic pathway was responsible for this event. The results show that macrophages stimulated with IL-4 + IL-13 up-regulate ASE I and cationic amino acid transporter 2B, causing a rapid reduction of extracellular levels of l-arginine and inducing decreased expression of CD3ζ and diminished proliferation in normal T lymphocytes. Competitive inhibitors of ASE I or the addition of excess l-arginine lead to the re-expression of CD3ζ and recovery of T cell proliferation. In contrast, inducible nitric oxide synthase or ASE II failed to significantly reduce the extracellular levels of l-arginine and modulate CD3ζ expression. These results may provide new insights into the mechanisms leading to T cell dysfunction and the down-regulation of CD3ζ in cancer and chronic infectious diseases.

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“…Arginine has many effects upon the immune system and has been shown to enhance immune function. 23 It is important for normal T and B lymphocyte and macrophage functions. Arginine is thymotrophic, and arginine supplementation decreases the thymolytic effect of stress.…”

Section: Other Metabolites Of Argininementioning

confidence: 99%

Arginine: Mediator or Modulator of Sepsis?

et al. 2004

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Arginine is a conditionally essential amino acid that plays pivotal roles in maintaining body homeostasis. Arginine is a substrate for protein synthesis but can also be metabolized to various bioactive compounds that include nitric oxide, ornithine, polyamines, creatine phosphate, agmatine, and dimethylarginines. Arginine produces physiologic effects via nitric oxide dependent and independent pathways. Nitric oxide is important for the modulation of vascular tone, inflammation, immune function, endothelial function, platelet and leukocyte adherence, and neurotransmission. Nitric oxide modulates many biochemical processes important for the response to sepsis. Arginine, independent of nitric oxide, is important for growth, wound healing, cardiovascular function, immune function, inflammatory responses, energy metabolism, urea cycle function, and other metabolic processes. Arginine supplementation improves outcomes in animals with sepsis, wounds, ischemia-reperfusion injury, and following thermal injury. Enteral administration of arginine improves endothelial function but has little effect upon hemodynamics during human sepsis. An analysis of clinical studies using enteral formulas with supplemental arginine suggests benefits upon outcome, with no evidence of significant detrimental effects.

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High arginine levels in intravenous hyperalimentation abrogate post-traumatic immune suppression

Cited by 72 publications

References 2 publications

Arginase, Prostaglandins, and Myeloid-Derived Suppressor Cells in Renal Cell Carcinoma

Arginase, Prostaglandins, and Myeloid-Derived Suppressor Cells in Renal Cell Carcinoma

l-Arginine Consumption by Macrophages Modulates the Expression of CD3ζ Chain in T Lymphocytes

Arginine: Mediator or Modulator of Sepsis?

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