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Plerixafor Compared with G-CSF Alloreactivity of T Cells Mobilized

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Plerixafor Compared with G-CSF Alloreactivity of T Cells Mobilized Differences in the Phenotype, Cytokine Gene Expression Profiles, and In Vivo Alloreactivity of T Cells Mobilized with Plerixafor Compared with G-CSF This information is current as of September 23, 2021. Andreas Lundqvist, Aleah L. Smith, Yoshiyuki Takahashi, Susan Wong, Erkut Bahceci, Lisa Cook, Catalina Ramos, Abdul Tawab, J. Philip McCoy, Jr., Elizabeth J. Read, Hanh M. Khuu, Charles D. Bolan, Jungnam Joo, Nancy Geller, Susan F. Leitman, Gary Calandra, Cynthia Dunbar, Roger Kurlander and Richard W. Childs Downloaded from J Immunol 2013; 191:6241-6249; Prepublished online 15 November 2013; doi: 10.4049/jimmunol.1301148 http://www.jimmunol.org/content/191/12/6241 http://www.jimmunol.org/ Supplementary http://www.jimmunol.org/content/suppl/2013/11/18/jimmunol.130114 Material 8.DC1 References This article cites 44 articles, 20 of which you can access for free at: http://www.jimmunol.org/content/191/12/6241.full#ref-list-1 by guest on September 23, 2021 Why The JI? Submit online. • Rapid Reviews! 30 days* from submission to initial decision • No Triage! Every submission reviewed by practicing scientists • Fast Publication! 4 weeks from acceptance to publication *average Subscription Information about subscribing to The Journal of Immunology is online at: http://jimmunol.org/subscription Permissions Submit copyright permission requests at: http://www.aai.org/About/Publications/JI/copyright.html Email Alerts Receive free email-alerts when new articles cite this article. Sign up at: http://jimmunol.org/alerts The Journal of Immunology is published twice each month by The American Association of Immunologists, Inc., 1451 Rockville Pike, Suite 650, Rockville, MD 20852 All rights reserved. Print ISSN: 0022-1767 Online ISSN: 1550-6606. The Journal of Immunology Differences in the Phenotype, Cytokine Gene Expression Profiles, and In Vivo Alloreactivity of T Cells Mobilized with Plerixafor Compared with G-CSF Andreas Lundqvist,*,† Aleah L. Smith,* Yoshiyuki Takahashi,‡ Susan Wong,* Erkut Bahceci,x Lisa Cook,* Catalina Ramos,* Abdul Tawab,{ J. Philip McCoy, Jr.,* Elizabeth J. Read,‖ Hanh M. Khuu,‖ Charles D. Bolan,‖ Jungnam Joo,‖ Nancy Geller,‖ Susan F. Leitman,‖ Gary Calandra,# Cynthia Dunbar,* Roger Kurlander,{ and Richard W. Childs* + Plerixafor (Mozobil) is a CXCR4 antagonist that rapidly mobilizes CD34 cells into circulation. Recently, plerixafor has been used Downloaded from as a single agent to mobilize peripheral blood stem cells for allogeneic hematopoietic cell transplantation. Although G-CSF mobilization is known to alter the phenotype and cytokine polarization of transplanted T cells, the effects of plerixafor mobili- zation on T cells have not been well characterized. In this study, we show that alterations in the T cell phenotype and cytokine gene expression profiles characteristic of G-CSF mobilization do not occur after mobilization with plerixafor. Compared with non- mobilized T cells, plerixafor-mobilized T cells had similar phenotype, mixed lymphocyte reactivity, and Foxp3 gene expression + levels in CD4 T cells, and did not undergo a change in expression levels of 84 genes associated with Th1/Th2/Th3 pathways. In http://www.jimmunol.org/ contrast with plerixafor, G-CSF mobilization decreased CD62L expression on both CD4 and CD8+ T cells and altered expression levels of 16 cytokine-associated genes in CD3+ T cells. To assess the clinical relevance of these findings, we explored a murine model of graft-versus-host disease in which transplant recipients received plerixafor or G-CSF mobilized allograft from MHC- matched, minor histocompatibility–mismatched donors; recipients of plerixafor mobilized peripheral blood stem cells had a sig- nificantly higher incidence of skin graft-versus-host disease compared with mice receiving G-CSF mobilized transplants (100 versus 50%, respectively, p = 0.02). These preclinical data show plerixafor, in contrast with G-CSF, does not alter the phenotype and cytokine polarization of T cells, which raises the possibility that T cell–mediated immune sequelae of allogeneic transplan- tation in humans may differ when donor allografts are mobilized with plerixafor compared with G-CSF. The Journal of by guest on September 23, 2021 Immunology, 2013, 191: 6241–6249. or adults with malignancies, mobilized peripheral blood quate numbers of peripheral blood stem cells (PBSCs) from progenitor cells (PBPC) are the preferred source of he- healthy donors, 5–10% of patients will mobilize poorly, necessi- F matopoietic stem cells (HSCs) for autologous transplants tating multiple large-volume apheresis or bone marrow harvesting and matched sibling allogeneic transplants because PBPCs engraft (2). Although G-CSF is generally well tolerated in healthy donors, faster than bone marrow–derived progenitor cells and are techni- it frequently causes bone pain, headache, myalgia, and in rare cally easier to collect (1). The administration of G-CSF results in circumstances, life-threatening adverse effects such as stroke, myo- successful mobilization of PBPCs in most healthy donors. Al- cardial infarction, and splenic rupture (3). The number of lym- though most regimens using G-CSF succeed in collecting ade- phocytes contained in G-CSF mobilized PBPC grafts is ∼10–15 times higher than BM grafts (4, 5). Despite containing substan- tially higher numbers of T cells, several prospective, randomized *Hematology Branch, National Heart, Lung and Blood Institute, National Institutes trials have shown that the incidence of acute graft-versus-host of Health, Bethesda, MD 20892; †Department of Oncology-Pathology, Karolinska Institutet, Stockholm S-17176, Sweden; ‡Nagoya University, Graduate School of disease (GVHD) is not higher in recipients of G-CSF mobilized x Medicine, Nagoya 466-8550, Japan; Section of Medical Oncology, Yale University PBPC allografts compared with BM allografts (4, 6–10). Although School of Medicine, New Haven, CT 06520; {Department of Laboratory Medicine, Clinical Center, National Institutes of Health, Bethesda, MD 20892; ‖Department of a number of mechanisms have been postulated to account for this Transfusion Medicine, Clinical Center, National Institutes of Health, Bethesda, MD phenomenon, alterations in cytokine-related genes in T cells mo- # 20892; and Sanofi Oncology, Cambridge, MA 02139 bilized with G-CSF including a polarization toward a type 2 cy- Received for publication May 13, 2013. Accepted for publication October 7, 2013. tokine (Th2) response is thought to play a pivotal role in reducing This work was supported by the intramural research program of the National Insti- the ability of T cells to trigger acute GVHD (11–14). The distinct tutes of Health, National Heart, Lung, and Blood Institute, Hematology Branch and cytokine production profile of Th2 cells has also been shown in the Swedish and European Research Councils (A.L.). animal models to contribute to the pathogenesis of chronic GVHD, Address correspondence and reprint requests to Dr. Richard Childs, Hematology Branch, National Heart, Lung and Blood Institute, National Institutes of Health, whichhasbeenshowninrandomizedtrialstooccurmorecom- 10CRC, 3-5330, Bethesda, MD 20892. E-mail address: [email protected] monly with G-CSF mobilized transplants compared with bone mar- The online version of this article contains supplemental material. row transplants. Abbreviations used in this article: a-HCT, allogeneic hematopoietic cell transplanta- Plerixafor (Mozobil) is a bicyclam compound that inhibits the tion; GVHD, graft-versus-host disease; KLS, c-Kit+/Lin-/sca-1+; NHLBI, National interaction of stromal cell–derived factor-1 (SDF-1) to its cognate Heart, Lung and Blood Institute; PBPC, peripheral blood progenitor cell; PBSC, + peripheral blood stem cell; SDF-1, stromal cell–derived factor-1; Treg, regulatory receptor CXCR4 (15, 16). CXCR4 is present on CD34 hemato- T cell. poietic progenitor cells, and its interaction with SDF-1 plays www.jimmunol.org/cgi/doi/10.4049/jimmunol.1301148 6242 EFFECT OF PLERIXAFOR MOBILIZATION ON LYMPHOCYTES a pivotal role in the homing of CD34+ cells in the bone marrow whole blood was incubated for 30 min at 4˚C with Abs. Each experiment (17, 18). Inhibition of CXCR4–SDF-1 binding by plerixafor re- was performed using the appropriate isotype controls. After incubation, leases CD34+ cells into the circulation, allowing them to be col- erythrocytes in these samples were lysed (Whole Blood Lysing Reagent; Coulter, Fullerton, CA), washed twice, and then fixed with paraformal- lected easily by apheresis (19). The addition of plerixafor to G-CSF dehyde. All samples were analyzed by using a CYAN MLE cytometer (Dako- has a potent synergistic effect on the mobilization PBPCs in pa- Cytomation, Ft. Collins, CO). Summit software (Dako-Cytomation) was used tients undergoing autologous transplantation. Plerixafor is approved for data acquisition and analysis. Mixtures of six fluorochrome-labeled mAbs in the United States in combination with G-CSF for hematopoietic were used in the same tube to assess the phenotype in different cell popu- lations. CD3-PE-Cy7, CD4-allophycocyanin-Cy7, CD8-PerCP, CD16-allo- stem cell mobilization and collection for subsequent autologous phycocyanin-Cy7, CD56-PE-Cy5, CD19-allophycocyanin, and CD34-FITC transplantation in non-Hodgkin’s lymphoma and multiple myeloma were used to gate T cell, B cell, NK cell, and hematopoietic progenitor cell patients. populations. CD57-FITC, CD27-FITC, CD62L-FITC, HLA-DR–FITC, Plerixafor given as a single agent can also mobilize substantial CD45RA-FITC, pan-TCRgd-FITC,
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