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Front Pharmacol ; 12: 735443, 2021.
Article in English | MEDLINE | ID: mdl-35111042


This review summarizes the structure and function of the alveolar unit, comprised of alveolar macrophage and epithelial cell types that work in tandem to respond to infection. Granulocyte-macrophage colony-stimulating factor (GM-CSF) helps to maintain the alveolar epithelium and pulmonary immune system under physiological conditions and plays a critical role in restoring homeostasis under pathologic conditions, including infection. Given the emergence of novel severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and global spread of coronavirus disease 2019 (COVID-19), with subsequent acute respiratory distress syndrome, understanding basic lung physiology in infectious diseases is especially warranted. This review summarizes clinical and preclinical data for GM-CSF in respiratory infections, and the rationale for sargramostim (yeast-derived recombinant human [rhu] GM-CSF) as adjunctive treatment for COVID-19 and other pulmonary infectious diseases.

Clin Immunol ; 228: 108731, 2021 07.
Article in English | MEDLINE | ID: mdl-33892201


In hosts with damaged or impaired immune systems such as those undergoing hematopoietic cell transplant (HCT) or intensive chemotherapy, breakthrough fungal infections can be fatal. Risk factors for breakthrough infections include severe neutropenia, use of corticosteroids, extended use of broad-spectrum antibiotics, and intensive care unit admission. An individual's cumulative state of immunosuppression directly contributes to the likelihood of experiencing increased infection risk. Incidence of invasive fungal infection (IFI) after HCT may be up to 5-8%. Early intervention may improve IFI outcomes, although many infections are resistant to standard therapies (voriconazole, caspofungin, micafungin, amphotericin B, posaconazole or itraconazole, as single agents or in combination). We review herein several contributing factors that may contribute to the net state of immunosuppression in recipients of HCT. We also review a new approach for IFI utilizing adjunctive therapy with sargramostim, a yeast-derived recombinant human granulocyte-macrophage colony-stimulating factor (rhu GM-CSF).

Granulocyte-Macrophage Colony-Stimulating Factor/therapeutic use , Hematopoietic Stem Cell Transplantation/adverse effects , Immunocompromised Host , Invasive Fungal Infections/drug therapy , Invasive Fungal Infections/etiology , Granulocyte-Macrophage Colony-Stimulating Factor/pharmacology , Hematopoietic Stem Cell Transplantation/methods , Humans , Invasive Fungal Infections/metabolism , Recombinant Proteins/pharmacology , Recombinant Proteins/therapeutic use , Transplantation, Homologous , Treatment Outcome
Clin Immunol ; 210: 108292, 2020 01.
Article in English | MEDLINE | ID: mdl-31676420


Granulocyte-macrophage-colony stimulating factor (GM-CSF), can direct the activation, proliferation and differentiation of myeloid-derived cells. It is also responsible for maturation and function of professional antigen presenting cells thereby impacting adaptive immune responses, while assisting to maintain epithelial barrier function. GM-CSF in combination with other endogenous cytokines and secondary stimuli, such as tumor necrosis factor can modulate pro-inflammatory monocyte priming via chromatin remodeling and enhanced transcriptional responses, a concept termed "trained immunity". An increase in the incidence of opportunistic fungal infections was recently reported in patients with hematological cancers receiving treatment with the BTK inhibitor, Ibrutinib. Tec Kinase BTK is known to influence the expression of GM-CSFRα and regulates downstream signaling pathways, suggesting a role for GM-CSF in maintenance of defense against fungal infections in immune competent hosts. Further examination of the potential mechanism(s) of action for naturally occurring GM-CSF and recombinant human GM-CSF (rhu-GM-CSF) expressed in yeast (sargramostim) are reviewed.

Granulocyte-Macrophage Colony-Stimulating Factor/metabolism , Immunotherapy/methods , Infections/therapy , Saccharomyces cerevisiae/metabolism , Animals , Chromatin Assembly and Disassembly/drug effects , Granulocyte-Macrophage Colony-Stimulating Factor/genetics , Granulocyte-Macrophage Colony-Stimulating Factor/therapeutic use , Humans , Immunity/drug effects , Immunomodulation , Infections/immunology , Inflammation , Recombinant Proteins/genetics , Recombinant Proteins/metabolism , Recombinant Proteins/therapeutic use , Saccharomyces cerevisiae/genetics , Tumor Necrosis Factor-alpha/therapeutic use