Dampened inflammatory signalling and myeloid-derived suppressor-like cell accumulation reduces circulating monocytic HLA-DR density and may associate with malignancy risk in long-term renal transplant recipients
Background: Malignancy is a major cause of morbidity and mortality in transplant recipients. Identification of those at highest risk could facilitate pre-emptive intervention such as reduction of immunosuppression. Reduced circulating monocytic HLA-DR density is a marker of immune depression in the...
| Main Authors: | , , , , |
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| Format: | Journal article |
| Language: | English |
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Frontiers Media SA
2022
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| _version_ | 1797107393578926080 |
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| author | Bottomley, MJ Harden, PN Wood, KJ Hester, J Issa, F |
| author_facet | Bottomley, MJ Harden, PN Wood, KJ Hester, J Issa, F |
| author_sort | Bottomley, MJ |
| collection | OXFORD |
| description | Background: Malignancy is a major cause of morbidity and mortality in transplant recipients. Identification of those at highest risk could facilitate pre-emptive intervention such as reduction of immunosuppression. Reduced circulating monocytic HLA-DR density is a marker of immune depression in the general population and associates with poorer outcome in critical illness. It has recently been used as a safety marker in adoptive cell therapy trials in renal transplantation. Despite its potential as a marker of dampened immune responses, factors that impact upon monocytic HLA-DR density and the long-term clinical sequelae of this have not been assessed in transplant recipients.
Methods: A cohort study of stable long-term renal transplant recipients was undertaken. Serial circulating monocytic HLA-DR density and other leucocyte populations were quantified by flow cytometry. Gene expression of monocytes was performed using the Nanostring nCounter platform, and 13-plex cytokine bead array used to quantify serum concentrations. The primary outcome was malignancy development during one-year follow-up. Risk of malignancy was calculated by univariate and multivariate proportionate hazards modelling with and without adjustment for competing risks.
Results: Monocytic HLA-DR density was stable in long-term renal transplant recipients (n=135) and similar to non-immunosuppressed controls (n=29), though was suppressed in recipients receiving prednisolone. Decreased mHLA-DRd was associated with accumulation of CD14+CD11b+CD33+HLA-DRlo monocytic myeloid-derived suppressor-like cells. Pathway analysis revealed downregulation of pathways relating to cytokine and chemokine signalling in monocytes with low HLA-DR density; however serum concentrations of major cytokines did not differ between these groups. There was an independent increase in malignancy risk during follow-up with decreased HLA-DR density.
Conclusions: Dampened chemokine and cytokine signalling drives a stable reduction in monocytic HLA-DR density in long-term transplant recipients and associates with subsequent malignancy risk. This may function as a novel marker of excess immunosuppression. Further study is needed to understand the mechanism behind this association.
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| first_indexed | 2024-03-07T07:13:55Z |
| format | Journal article |
| id | oxford-uuid:77ffc83b-e6cb-421c-a6a0-01c457025167 |
| institution | University of Oxford |
| language | English |
| last_indexed | 2024-03-07T07:13:55Z |
| publishDate | 2022 |
| publisher | Frontiers Media SA |
| record_format | dspace |
| spelling | oxford-uuid:77ffc83b-e6cb-421c-a6a0-01c4570251672022-07-28T07:08:02ZDampened inflammatory signalling and myeloid-derived suppressor-like cell accumulation reduces circulating monocytic HLA-DR density and may associate with malignancy risk in long-term renal transplant recipientsJournal articlehttp://purl.org/coar/resource_type/c_dcae04bcuuid:77ffc83b-e6cb-421c-a6a0-01c457025167EnglishSymplectic ElementsFrontiers Media SA2022Bottomley, MJHarden, PNWood, KJHester, JIssa, FBackground: Malignancy is a major cause of morbidity and mortality in transplant recipients. Identification of those at highest risk could facilitate pre-emptive intervention such as reduction of immunosuppression. Reduced circulating monocytic HLA-DR density is a marker of immune depression in the general population and associates with poorer outcome in critical illness. It has recently been used as a safety marker in adoptive cell therapy trials in renal transplantation. Despite its potential as a marker of dampened immune responses, factors that impact upon monocytic HLA-DR density and the long-term clinical sequelae of this have not been assessed in transplant recipients. Methods: A cohort study of stable long-term renal transplant recipients was undertaken. Serial circulating monocytic HLA-DR density and other leucocyte populations were quantified by flow cytometry. Gene expression of monocytes was performed using the Nanostring nCounter platform, and 13-plex cytokine bead array used to quantify serum concentrations. The primary outcome was malignancy development during one-year follow-up. Risk of malignancy was calculated by univariate and multivariate proportionate hazards modelling with and without adjustment for competing risks. Results: Monocytic HLA-DR density was stable in long-term renal transplant recipients (n=135) and similar to non-immunosuppressed controls (n=29), though was suppressed in recipients receiving prednisolone. Decreased mHLA-DRd was associated with accumulation of CD14+CD11b+CD33+HLA-DRlo monocytic myeloid-derived suppressor-like cells. Pathway analysis revealed downregulation of pathways relating to cytokine and chemokine signalling in monocytes with low HLA-DR density; however serum concentrations of major cytokines did not differ between these groups. There was an independent increase in malignancy risk during follow-up with decreased HLA-DR density. Conclusions: Dampened chemokine and cytokine signalling drives a stable reduction in monocytic HLA-DR density in long-term transplant recipients and associates with subsequent malignancy risk. This may function as a novel marker of excess immunosuppression. Further study is needed to understand the mechanism behind this association. |
| spellingShingle | Bottomley, MJ Harden, PN Wood, KJ Hester, J Issa, F Dampened inflammatory signalling and myeloid-derived suppressor-like cell accumulation reduces circulating monocytic HLA-DR density and may associate with malignancy risk in long-term renal transplant recipients |
| title | Dampened inflammatory signalling and myeloid-derived suppressor-like cell accumulation reduces circulating monocytic HLA-DR density and may associate with malignancy risk in long-term renal transplant recipients |
| title_full | Dampened inflammatory signalling and myeloid-derived suppressor-like cell accumulation reduces circulating monocytic HLA-DR density and may associate with malignancy risk in long-term renal transplant recipients |
| title_fullStr | Dampened inflammatory signalling and myeloid-derived suppressor-like cell accumulation reduces circulating monocytic HLA-DR density and may associate with malignancy risk in long-term renal transplant recipients |
| title_full_unstemmed | Dampened inflammatory signalling and myeloid-derived suppressor-like cell accumulation reduces circulating monocytic HLA-DR density and may associate with malignancy risk in long-term renal transplant recipients |
| title_short | Dampened inflammatory signalling and myeloid-derived suppressor-like cell accumulation reduces circulating monocytic HLA-DR density and may associate with malignancy risk in long-term renal transplant recipients |
| title_sort | dampened inflammatory signalling and myeloid derived suppressor like cell accumulation reduces circulating monocytic hla dr density and may associate with malignancy risk in long term renal transplant recipients |
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