Utility of monocyte HLA-DR and rationale for therapeutic GM-CSF in sepsis immunoparalysis
Sepsis, a heterogeneous clinical syndrome, features a systemic inflammatory response to tissue injury or infection, followed by a state of reduced immune responsiveness. Measurable alterations occur in both the innate and adaptive immune systems. Immunoparalysis, an immunosuppressed state, associate...
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| Format: | Article |
| Language: | English |
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Frontiers Media S.A.
2023-02-01
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| Series: | Frontiers in Immunology |
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| Online Access: | https://www.frontiersin.org/articles/10.3389/fimmu.2023.1130214/full |
| _version_ | 1811170064847601664 |
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| author | Ila Joshi Walter P. Carney Edwin P. Rock |
| author_facet | Ila Joshi Walter P. Carney Edwin P. Rock |
| author_sort | Ila Joshi |
| collection | DOAJ |
| description | Sepsis, a heterogeneous clinical syndrome, features a systemic inflammatory response to tissue injury or infection, followed by a state of reduced immune responsiveness. Measurable alterations occur in both the innate and adaptive immune systems. Immunoparalysis, an immunosuppressed state, associates with worsened outcomes, including multiple organ dysfunction syndrome, secondary infections, and increased mortality. Multiple immune markers to identify sepsis immunoparalysis have been proposed, and some might offer clinical utility. Sepsis immunoparalysis is characterized by reduced lymphocyte numbers and downregulation of class II human leukocyte antigens (HLA) on innate immune monocytes. Class II HLA proteins present peptide antigens for recognition by and activation of antigen-specific T lymphocytes. One monocyte class II protein, mHLA-DR, can be measured by flow cytometry. Downregulated mHLA-DR indicates reduced monocyte responsiveness, as measured by ex-vivo cytokine production in response to endotoxin stimulation. Our literature survey reveals low mHLA-DR expression on peripheral blood monocytes correlates with increased risks for infection and death. For mHLA-DR, 15,000 antibodies/cell appears clinically acceptable as the lower limit of immunocompetence. Values less than 15,000 antibodies/cell are correlated with sepsis severity; and values at or less than 8000 antibodies/cell are identified as severe immunoparalysis. Several experimental immunotherapies have been evaluated for reversal of sepsis immunoparalysis. In particular, sargramostim, a recombinant human granulocyte-macrophage colony-stimulating factor (rhu GM-CSF), has demonstrated clinical benefit by reducing hospitalization duration and lowering secondary infection risk. Lowered infection risk correlates with increased mHLA-DR expression on peripheral blood monocytes in these patients. Although mHLA-DR has shown promising utility for identifying sepsis immunoparalysis, absence of a standardized, analytically validated method has thus far prevented widespread adoption. A clinically useful approach for patient inclusion and identification of clinically correlated output parameters could address the persistent high unmet medical need for effective targeted therapies in sepsis. |
| first_indexed | 2024-04-10T16:51:21Z |
| format | Article |
| id | doaj.art-d018f60feaa046a7a72fc06876a22736 |
| institution | Directory Open Access Journal |
| issn | 1664-3224 |
| language | English |
| last_indexed | 2024-04-10T16:51:21Z |
| publishDate | 2023-02-01 |
| publisher | Frontiers Media S.A. |
| record_format | Article |
| series | Frontiers in Immunology |
| spelling | doaj.art-d018f60feaa046a7a72fc06876a227362023-02-07T16:16:35ZengFrontiers Media S.A.Frontiers in Immunology1664-32242023-02-011410.3389/fimmu.2023.11302141130214Utility of monocyte HLA-DR and rationale for therapeutic GM-CSF in sepsis immunoparalysisIla Joshi0Walter P. Carney1Edwin P. Rock2Development and Regulatory Department, Partner Therapeutics, Inc., Lexington, MA, United StatesWalt Carney Biomarkers Consulting, LLC., North Andover, MA, United StatesDevelopment and Regulatory Department, Partner Therapeutics, Inc., Lexington, MA, United StatesSepsis, a heterogeneous clinical syndrome, features a systemic inflammatory response to tissue injury or infection, followed by a state of reduced immune responsiveness. Measurable alterations occur in both the innate and adaptive immune systems. Immunoparalysis, an immunosuppressed state, associates with worsened outcomes, including multiple organ dysfunction syndrome, secondary infections, and increased mortality. Multiple immune markers to identify sepsis immunoparalysis have been proposed, and some might offer clinical utility. Sepsis immunoparalysis is characterized by reduced lymphocyte numbers and downregulation of class II human leukocyte antigens (HLA) on innate immune monocytes. Class II HLA proteins present peptide antigens for recognition by and activation of antigen-specific T lymphocytes. One monocyte class II protein, mHLA-DR, can be measured by flow cytometry. Downregulated mHLA-DR indicates reduced monocyte responsiveness, as measured by ex-vivo cytokine production in response to endotoxin stimulation. Our literature survey reveals low mHLA-DR expression on peripheral blood monocytes correlates with increased risks for infection and death. For mHLA-DR, 15,000 antibodies/cell appears clinically acceptable as the lower limit of immunocompetence. Values less than 15,000 antibodies/cell are correlated with sepsis severity; and values at or less than 8000 antibodies/cell are identified as severe immunoparalysis. Several experimental immunotherapies have been evaluated for reversal of sepsis immunoparalysis. In particular, sargramostim, a recombinant human granulocyte-macrophage colony-stimulating factor (rhu GM-CSF), has demonstrated clinical benefit by reducing hospitalization duration and lowering secondary infection risk. Lowered infection risk correlates with increased mHLA-DR expression on peripheral blood monocytes in these patients. Although mHLA-DR has shown promising utility for identifying sepsis immunoparalysis, absence of a standardized, analytically validated method has thus far prevented widespread adoption. A clinically useful approach for patient inclusion and identification of clinically correlated output parameters could address the persistent high unmet medical need for effective targeted therapies in sepsis.https://www.frontiersin.org/articles/10.3389/fimmu.2023.1130214/fullsepsisimmunoparalysisimmunosuppressiongranulocyte-macrophage colony-stimulating factorhuman leukocyte antigen-DRmonocytes |
| spellingShingle | Ila Joshi Walter P. Carney Edwin P. Rock Utility of monocyte HLA-DR and rationale for therapeutic GM-CSF in sepsis immunoparalysis Frontiers in Immunology sepsis immunoparalysis immunosuppression granulocyte-macrophage colony-stimulating factor human leukocyte antigen-DR monocytes |
| title | Utility of monocyte HLA-DR and rationale for therapeutic GM-CSF in sepsis immunoparalysis |
| title_full | Utility of monocyte HLA-DR and rationale for therapeutic GM-CSF in sepsis immunoparalysis |
| title_fullStr | Utility of monocyte HLA-DR and rationale for therapeutic GM-CSF in sepsis immunoparalysis |
| title_full_unstemmed | Utility of monocyte HLA-DR and rationale for therapeutic GM-CSF in sepsis immunoparalysis |
| title_short | Utility of monocyte HLA-DR and rationale for therapeutic GM-CSF in sepsis immunoparalysis |
| title_sort | utility of monocyte hla dr and rationale for therapeutic gm csf in sepsis immunoparalysis |
| topic | sepsis immunoparalysis immunosuppression granulocyte-macrophage colony-stimulating factor human leukocyte antigen-DR monocytes |
| url | https://www.frontiersin.org/articles/10.3389/fimmu.2023.1130214/full |
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