Early intestinal microbial features are associated with CD4 T-cell recovery after allogeneic hematopoietic transplant

Oriana Miltiadous; Nicholas R. Waters; Hana Andrlová; Anqi Dai; Chi L. Nguyen; Marina Burgos da Silva; Sarah Lindner; John Slingerland; Paul Giardina; Annelie Clurman; Gabriel K. Armijo; Antonio L.C. Gomes; Madhavi Lakkaraja; Peter Maslak; Michael Scordo; Roni Shouval; Anna Staffas; Richard O'Reilly; Ying Taur; Susan Prockop; Jaap Jan Boelens; Sergio Giralt; Miguel Angel Perales; Sean M. Devlin; Jonathan U. Peled; Kate A. Markey; Marcel R.M. van den Brink

doi:10.1182/blood.2021014255

Early intestinal microbial features are associated with CD4 T-cell recovery after allogeneic hematopoietic transplant

Oriana Miltiadous, Nicholas R. Waters, Hana Andrlová, Anqi Dai, Chi L. Nguyen, Marina Burgos da Silva, Sarah Lindner, John Slingerland, Paul Giardina, Annelie Clurman, Gabriel K. Armijo, Antonio L.C. Gomes, Madhavi Lakkaraja, Peter Maslak, Michael Scordo, Roni Shouval, Anna Staffas, Richard O'Reilly, Ying Taur, Susan ProckopJaap Jan Boelens, Sergio Giralt, Miguel Angel Perales, Sean M. Devlin, Jonathan U. Peled, Kate A. Markey, Marcel R.M. van den Brink

Research output: Contribution to journal › Article › peer-review

30 Scopus citations

Abstract

Low intestinal microbial diversity is associated with poor outcomes after allogeneic hematopoietic cell transplantation (HCT). Using 16S rRNA sequencing of 2067 stool samples and flow cytometry data from 2370 peripheral blood samples drawn from 894 patients who underwent allogeneic HCT, we have linked features of the early post-HCT microbiome with subsequent immune cell recovery. We examined lymphocyte recovery and microbiota features in recipients of both unmodified and CD34-selected allografts. We observed that fecal microbial diversity was an independent predictor of CD4 T-cell count 3 months after HCT in recipients of a CD34-selected allograft, who are dependent on de novo lymphopoiesis for their immune recovery. In multivariate models using clinical factors and microbiota features, we consistently observed that increased fecal relative abundance of genus Staphylococcus during the early posttransplant period was associated with worse CD4 T-cell recovery. Our observations suggest that the intestinal bacteria, or the factors they produce, can affect early lymphopoiesis and the homeostasis of allograft-derived T cells after transplantation.

Original language	English
Pages (from-to)	2758-2769
Number of pages	12
Journal	Blood
Volume	139
Issue number	18
DOIs	https://doi.org/10.1182/blood.2021014255
State	Published - 5 May 2022
Externally published	Yes

Bibliographical note

Publisher Copyright:
© 2022 American Society of Hematology

Funding

Conflict-of-interest disclosure: P.M. receives research funding from BD Biosciences. R.S. is a consultant for Medexus and MyBiotics. S.P. receives support for the conduct of clinical trials from Atara Biotherapeutics, Jasper Therapeutics, and AlloVir; serves on advisory boards for Neovii and ADMA, and is an inventor on intellectual property licensed to Atara by MSKCC, with all rights assigned to MSKCC. J.J.B. is a consultant for Race Oncology, Avrobio, Advanced Clinical, and Omeros. M.-A.P. reports honoraria from AbbVie, Astellas, Bristol-Myers Squibb, Celgene, Equilium, Incyte, Karyopharm, Kite/Gilead, Merck, Miltenyi Biotec, MorphoSys, Novartis, Nektar Therapeutics, Omeros, Takeda, VectivBio AG, and Vor Biopharma and serves on data safety management boards for Cidara Therapeutics, Medigene, Sellas Life Sciences, and Servier, and the scientific advisory board of NexImmune; has ownership interests in NexImmune and Omeros; has received research support for clinical trials from Incyte, Kite/Gilead, Miltenyi Biotec, and Novartis; serves in a volunteer capacity as a member of the Board of Directors of the American Society for Transplantation and Cellular Therapy (ASTCT) and Be The Match (National Marrow Donor Program, NMDP), and on the Center for International Blood and Marrow Transplant Research (CIBMTR) Cellular Immunotherapy Data Resource (CIDR) Executive Committee. M.S. served as a paid consultant for McKinsey and Company, Angiocrine Bioscience, Inc, and Omeros Corporation; received research funding from Angiocrine Bioscience, Inc and Omeros Corporation; served on ad hoc advisory boards for Kite/Gilead; and received a 1-time speaker's fee from i3Health for a continuing medical education speaking engagement. J.U.P. reports research funding, intellectual property fees, and travel reimbursement from Seres Therapeutics and consulting fees from Da Volterra, CSL Behring, and MaaT Pharma; serving on an advisory board of and holding equity in Postbiotics Plus Research; and filing intellectual property applications related to the microbiome (reference numbers 62/843 849, 62/977 908, and 15/756 845). M.R.M.v.d.B. has received research support and stock options from Seres Therapeutics and stock options from Notch Therapeutics and Pluto Therapeutics and royalties from Wolters Kluwer; has consulted, received honoraria from, or participated on advisory boards for Seres Therapeutics, WindMIL Therapeutics, Rheos Medicines, Merck and Co, Inc, Magenta Therapeutics, Frazier Healthcare Partners, Nektar Therapeutics, Notch Therapeutics, Forty Seven Inc, Ceramedix, Lygenesis, Pluto Therapeutics, GlaskoSmithKline, Da Volterra, Vor Biopharma, Novartis (spouse), Synthekine (spouse), and Beigene (spouse); has intellectual property licensing with Seres Therapeutics and Juno Therapeutics; and holds a fiduciary role on the Foundation Board of DKMS (a nonprofit organization). K.A.M. serves on the advisory board of and holds equity in Postbiotics Plus Research. Memorial Sloan Kettering Cancer Center (MSKCC) has financial interests relative to SeresTherapeutics. The remaining authors declare no competing financial interests. This work was supported in part by the National Institutes of Health (NIH), National Cancer Institute (NCI) Cancer Center Support Grant P30-CA008748 and NIH, NCI grant P01-CA023766; by an American Society of Clinical Oncology (ASCO) young investigator award, a Hyundai Hope on Wheels young investigator award, a Cycle for Survival Equinox Innovation award, and a Collaborative Pediatric Cancer Research Program Award (O.M.); the Deutsche Forschungsgemeinschaft (DFG) and American Society for Transplantation and Cellular Therapy (ASTCT) (H.A.), funding from NIH, National Heart, Lung, and Blood Institute (NHLBI) grant K08HL143189 and the Parker Institute for Cancer Immunotherapy at Memorial Sloan Kettering Cancer Center (J.U.P.); NCI awards, R01-CA228358 and R01- CA228308, NHLBI award R01-HL125571, R01-HL123340, National Institute of Aging (NIA) award Project 2 P01-AG052359, National institute of Allergy and Infectious Diseases (NIAID) award U01 AI124275, Tri-Institutional Stem Cell Initiative award 2016-013, The Lymphoma Foundation, The Susan and Peter Solomon Divisional Genomics Program, and the Parker Institute for Cancer Immunotherapy at Memorial Sloan Kettering Cancer Center (M.R.M.v.d.B.); and the DKMS (Deutsche KnochenMarkSpenderdatei or German Bone Marrow Donor File) and the Parker Institute for Cancer Immunotherapy (K.A.M.).

Funders	Funder number
Angiocrine Bioscience, Inc and Omeros Corporation
Cycle for Survival Equinox Innovation
McKinsey and Company
National Institutes of Health
National Institute on Aging	2 P01-AG052359
National Heart, Lung, and Blood Institute	K08HL143189
National Cancer Institute	P01-CA023766, P30-CA008748
National Institute of Allergy and Infectious Diseases	2016-013, U01 AI124275
American Society of Clinical Oncology
Lymphoma Foundation
Parker Institute for Cancer Immunotherapy	R01- CA228308, R01-CA228358, R01-HL123340, R01-HL125571
American Society for Transplantation and Cellular Therapy
Angiocrine Bioscience
Omeros Corporation
Deutsche Forschungsgemeinschaft

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10.1182/blood.2021014255

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Miltiadous, O., Waters, N. R., Andrlová, H., Dai, A., Nguyen, C. L., Burgos da Silva, M., Lindner, S., Slingerland, J., Giardina, P., Clurman, A., Armijo, G. K., Gomes, A. L. C., Lakkaraja, M., Maslak, P., Scordo, M., Shouval, R., Staffas, A., O'Reilly, R., Taur, Y., ... van den Brink, M. R. M. (2022). Early intestinal microbial features are associated with CD4 T-cell recovery after allogeneic hematopoietic transplant. Blood, 139(18), 2758-2769. https://doi.org/10.1182/blood.2021014255

@article{29ba7a571876444d91ac106d97773ecb,

title = "Early intestinal microbial features are associated with CD4 T-cell recovery after allogeneic hematopoietic transplant",

abstract = "Low intestinal microbial diversity is associated with poor outcomes after allogeneic hematopoietic cell transplantation (HCT). Using 16S rRNA sequencing of 2067 stool samples and flow cytometry data from 2370 peripheral blood samples drawn from 894 patients who underwent allogeneic HCT, we have linked features of the early post-HCT microbiome with subsequent immune cell recovery. We examined lymphocyte recovery and microbiota features in recipients of both unmodified and CD34-selected allografts. We observed that fecal microbial diversity was an independent predictor of CD4 T-cell count 3 months after HCT in recipients of a CD34-selected allograft, who are dependent on de novo lymphopoiesis for their immune recovery. In multivariate models using clinical factors and microbiota features, we consistently observed that increased fecal relative abundance of genus Staphylococcus during the early posttransplant period was associated with worse CD4 T-cell recovery. Our observations suggest that the intestinal bacteria, or the factors they produce, can affect early lymphopoiesis and the homeostasis of allograft-derived T cells after transplantation.",

author = "Oriana Miltiadous and Waters, {Nicholas R.} and Hana Andrlov{\'a} and Anqi Dai and Nguyen, {Chi L.} and {Burgos da Silva}, Marina and Sarah Lindner and John Slingerland and Paul Giardina and Annelie Clurman and Armijo, {Gabriel K.} and Gomes, {Antonio L.C.} and Madhavi Lakkaraja and Peter Maslak and Michael Scordo and Roni Shouval and Anna Staffas and Richard O'Reilly and Ying Taur and Susan Prockop and Boelens, {Jaap Jan} and Sergio Giralt and Perales, {Miguel Angel} and Devlin, {Sean M.} and Peled, {Jonathan U.} and Markey, {Kate A.} and {van den Brink}, {Marcel R.M.}",

note = "Publisher Copyright: {\textcopyright} 2022 American Society of Hematology",

year = "2022",

month = may,

day = "5",

doi = "10.1182/blood.2021014255",

language = "אנגלית",

volume = "139",

pages = "2758--2769",

journal = "Blood",

issn = "0006-4971",

publisher = "Elsevier B.V.",

number = "18",

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Miltiadous, O, Waters, NR, Andrlová, H, Dai, A, Nguyen, CL, Burgos da Silva, M, Lindner, S, Slingerland, J, Giardina, P, Clurman, A, Armijo, GK, Gomes, ALC, Lakkaraja, M, Maslak, P, Scordo, M, Shouval, R, Staffas, A, O'Reilly, R, Taur, Y, Prockop, S, Boelens, JJ, Giralt, S, Perales, MA, Devlin, SM, Peled, JU, Markey, KA & van den Brink, MRM 2022, 'Early intestinal microbial features are associated with CD4 T-cell recovery after allogeneic hematopoietic transplant', Blood, vol. 139, no. 18, pp. 2758-2769. https://doi.org/10.1182/blood.2021014255

TY - JOUR

T1 - Early intestinal microbial features are associated with CD4 T-cell recovery after allogeneic hematopoietic transplant

AU - Miltiadous, Oriana

AU - Waters, Nicholas R.

AU - Andrlová, Hana

AU - Dai, Anqi

AU - Nguyen, Chi L.

AU - Burgos da Silva, Marina

AU - Lindner, Sarah

AU - Slingerland, John

AU - Giardina, Paul

AU - Clurman, Annelie

AU - Armijo, Gabriel K.

AU - Gomes, Antonio L.C.

AU - Lakkaraja, Madhavi

AU - Maslak, Peter

AU - Scordo, Michael

AU - Shouval, Roni

AU - Staffas, Anna

AU - O'Reilly, Richard

AU - Taur, Ying

AU - Prockop, Susan

AU - Boelens, Jaap Jan

AU - Giralt, Sergio

AU - Perales, Miguel Angel

AU - Devlin, Sean M.

AU - Peled, Jonathan U.

AU - Markey, Kate A.

AU - van den Brink, Marcel R.M.

PY - 2022/5/5

Y1 - 2022/5/5

N2 - Low intestinal microbial diversity is associated with poor outcomes after allogeneic hematopoietic cell transplantation (HCT). Using 16S rRNA sequencing of 2067 stool samples and flow cytometry data from 2370 peripheral blood samples drawn from 894 patients who underwent allogeneic HCT, we have linked features of the early post-HCT microbiome with subsequent immune cell recovery. We examined lymphocyte recovery and microbiota features in recipients of both unmodified and CD34-selected allografts. We observed that fecal microbial diversity was an independent predictor of CD4 T-cell count 3 months after HCT in recipients of a CD34-selected allograft, who are dependent on de novo lymphopoiesis for their immune recovery. In multivariate models using clinical factors and microbiota features, we consistently observed that increased fecal relative abundance of genus Staphylococcus during the early posttransplant period was associated with worse CD4 T-cell recovery. Our observations suggest that the intestinal bacteria, or the factors they produce, can affect early lymphopoiesis and the homeostasis of allograft-derived T cells after transplantation.

AB - Low intestinal microbial diversity is associated with poor outcomes after allogeneic hematopoietic cell transplantation (HCT). Using 16S rRNA sequencing of 2067 stool samples and flow cytometry data from 2370 peripheral blood samples drawn from 894 patients who underwent allogeneic HCT, we have linked features of the early post-HCT microbiome with subsequent immune cell recovery. We examined lymphocyte recovery and microbiota features in recipients of both unmodified and CD34-selected allografts. We observed that fecal microbial diversity was an independent predictor of CD4 T-cell count 3 months after HCT in recipients of a CD34-selected allograft, who are dependent on de novo lymphopoiesis for their immune recovery. In multivariate models using clinical factors and microbiota features, we consistently observed that increased fecal relative abundance of genus Staphylococcus during the early posttransplant period was associated with worse CD4 T-cell recovery. Our observations suggest that the intestinal bacteria, or the factors they produce, can affect early lymphopoiesis and the homeostasis of allograft-derived T cells after transplantation.

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Early intestinal microbial features are associated with CD4 T-cell recovery after allogeneic hematopoietic transplant

Abstract

Bibliographical note

Funding

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