Challenges and Opportunities for Biomarkers of Clinical Response to AHSCT in Autoimmunity
Kristina M Harris, Tingting Lu, Noha Lim, Laurence A Turka, Kristina M Harris, Tingting Lu, Noha Lim, Laurence A Turka
Abstract
Autoimmunity represents a broad category of diseases that involve a variety of organ targets and distinct autoantigens. For patients with autoimmune diseases who fail to respond to approved disease-modifying treatments, autologous hematopoietic stem cell transplantation (AHSCT) after high-dose immunosuppressive therapy provides an alternative strategy. Although more than 100 studies have been published on AHSCT efficacy in autoimmunity, the mechanisms that confer long-term disease remission as opposed to continued deterioration or disease reactivation remain to be determined. In a phase II clinical trial, high-dose immunosuppressive therapy combined with autologous CD34+ hematopoietic stem cell transplant in treatment-resistant, relapsing-remitting multiple sclerosis (RRMS) resulted in 69.2% of participants achieving long-term remission through 60 months follow-up. Flow cytometry data from the 24 transplanted participants in the high-dose immunosuppression and autologous stem cell transplantation for poor prognosis multiple sclerosis (HALT-MS) trial are presented to illustrate immune reconstitution out to 36 months in patients with aggressive RRMS treated with AHSCT and to highlight experimental challenges inherent in identifying biomarkers for relapse and long-term remission through 60 months follow-up. AHSCT induced changes in numbers of CD4 T cells and in the composition of CD4 and CD8 T cells that persisted through 36 months in participants who maintained disease remission through 60 months. However, changes in T cell phenotypes studied were unable to clearly discriminate durable remission from disease reactivation after AHSCT, possibly due to the small sample size, limited phenotypes evaluated in this real-time assay, and other limitations of the HALT-MS study population. Strategies and future opportunities for identifying biomarkers of clinical outcome to AHSCT in autoimmunity are also discussed.
Trial registration: ClinicalTrials.gov NCT00288626.
Keywords: T cells; autoimmunity; biomarkers; flow cytometry; immune cell reconstitution; immune tolerance; multiple sclerosis.
Figures
References
- Zeher M, Papp G, Nakken B, Szodoray P. Hematopoietic stem cell transplantation in autoimmune disorders: from immune-regulatory processes to clinical implications. Autoimmun Rev (2017) 16:817–25.10.1016/j.autrev.2017.05.020
- Alexander T, Arnold R, Hiepe F, Radbruch A. Resetting the immune system with immunoablation and autologous haematopoietic stem cell transplantation in autoimmune diseases. Clin Exp Rheumatol (2016) 34(4 Suppl 98):53–7.
- Muraro PA, Martin R, Mancardi GL, Nicholas R, Sormani MP, Saccardi R. Autologous haematopoietic stem cell transplantation for treatment of multiple sclerosis. Nat Rev Neurol (2017) 13:391–405.10.1038/nrneurol.2017.81
- Nash RA, Hutton GJ, Racke MK, Popat U, Devine SM, Steinmiller KC, et al. High-dose immunosuppressive therapy and autologous HCT for relapsing-remitting MS. Neurology (2017) 88:842–52.10.1212/WNL.0000000000003660
- Cencioni MT, Magliozzi R, Nicholas R, Ali R, Malik O, Reynolds R, et al. Programmed death 1 is highly expressed on CD8+ CD57+ T cells in patients with stable multiple sclerosis and inhibits their cytotoxic response to Epstein-Barr virus. Immunology (2017) 152:660–76.10.1111/imm.12808
- Arruda LCM, de Azevedo JTC, de Oliveira GLV, Scortegagna GT, Rodrigues ES, Palma PVB, et al. Immunological correlates of favorable long-term clinical outcome in multiple sclerosis patients after autologous hematopoietic stem cell transplantation. Clin Immunol (2016) 169:47–57.10.1016/j.clim.2016.06.005
- Malmegrim KC, de Azevedo JTC, Arruda LC, Abreu JR, Couri CE, de Oliveira GLV, et al. Immunological balance is associated with clinical outcome after autologous hematopoietic stem cell transplantation in type 1 diabetes. Front Immunol (2017) 8:167.10.3389/fimmu.2017.00167
- Abrahamsson SV, Angelini DF, Dubinsky AN, Morel E, Oh U, Jones JL, et al. Non-myeloablative autologous haematopoietic stem cell transplantation expands regulatory cells and depletes IL-17 producing mucosal-associated invariant T cells in multiple sclerosis. Brain (2013) 136:2888–903.10.1093/brain/awt182
- Bosch M, Khan FM, Storek J. Immune reconstitution after hematopoietic cell transplantation. Curr Opin Hematol (2012) 19:324–35.10.1097/MOH.0b013e328353bc7d
- Karnell FG, Lin D, Motley S, Duhen T, Lim N, Campbell DJ, et al. Reconstitution of immune cell populations in multiple sclerosis patients after autologous stem cell transplantation. Clin Exp Immunol (2017) 189:268–78.10.1111/cei.12985
- Muraro PA, Douek DC, Packer A, Chung K, Guenaga FJ, Cassiani-Ingoni R, et al. Thymic output generates a new and diverse TCR repertoire after autologous stem cell transplantation in multiple sclerosis patients. J Exp Med (2005) 201:805–16.10.1084/jem.20041679
- Baraut J, Grigore EI, Jean-Louis F, Khelifa SH, Durand C, Verrecchia F, et al. Peripheral blood regulatory T cells in patients with diffuse systemic sclerosis (SSc) before and after autologous hematopoietic SCT: a pilot study. Bone Marrow Transplant (2014) 49:349–54.10.1038/bmt.2013.202
- Ye L, Li L, Wan B, Yang M, Hong J, Gu W, et al. Immune response after autologous hematopoietic stem cell transplantation in type 1 diabetes mellitus. Stem Cell Res Ther (2017) 8:90.10.1186/s13287-017-0542-1
- Zhang L, Bertucci AM, Ramsey-Goldman R, Burt RK, Datta SK. Regulatory T cell (Treg) subsets return in patients with refractory lupus following stem cell transplantation, and TGF-beta-producing CD8+ Treg cells are associated with immunological remission of lupus. J Immunol (2009) 183:6346–58.10.4049/jimmunol.0901773
- Dubinsky AN, Burt RK, Martin R, Muraro PA. T-cell clones persisting in the circulation after autologous hematopoietic SCT are undetectable in the peripheral CD34+ selected graft. Bone Marrow Transplant (2010) 45:325–31.10.1038/bmt.2009.139
- Alexander T, Bondanza A, Muraro PA, Greco R, Saccardi R, Daikeler T, et al. SCT for severe autoimmune diseases: consensus guidelines of the European Society for Blood and Marrow Transplantation for immune monitoring and biobanking. Bone Marrow Transplant (2015) 50:173–80.10.1038/bmt.2014.251
- Voskuil J. How difficult is the validation of clinical biomarkers? F1000Res (2015) 4:101.10.12688/f1000research.6395.1
- Arruda LC, Lorenzi JC, Sousa AP, Zanette DL, Palma PV, Panepucci RA, et al. Autologous hematopoietic SCT normalizes miR-16, -155 and -142-3p expression in multiple sclerosis patients. Bone Marrow Transplant (2015) 50:380–9.10.1038/bmt.2014.277
- de Oliveira GL, Ferreira AF, Gasparotto EP, Kashima S, Covas DT, Guerreiro CT, et al. Defective expression of apoptosis-related molecules in multiple sclerosis patients is normalized early after autologous haematopoietic stem cell transplantation. Clin Exp Immunol (2017) 187:383–98.10.1111/cei.12895
- de Oliveira GL, Malmegrim KC, Ferreira AF, Tognon R, Kashima S, Couri CE, et al. Up-regulation of fas and fasL pro-apoptotic genes expression in type 1 diabetes patients after autologous haematopoietic stem cell transplantation. Clin Exp Immunol (2012) 168:291–302.10.1111/j.1365-2249.2012.04583.x
- Darlington PJ, Touil T, Doucet JS, Gaucher D, Zeidan J, Gauchat D, et al. Diminished Th17 (not Th1) responses underlie multiple sclerosis disease abrogation after hematopoietic stem cell transplantation. Ann Neurol (2013) 73:341–54.10.1002/ana.23784
- Sun W, Popat U, Hutton G, Zang YC, Krance R, Carrum G, et al. Characteristics of T-cell receptor repertoire and myelin-reactive T cells reconstituted from autologous haematopoietic stem-cell grafts in multiple sclerosis. Brain (2004) 127:996–1008.10.1093/brain/awh117
- Muraro PA, Robins H, Malhotra S, Howell M, Phippard D, Desmarais C, et al. T cell repertoire following autologous stem cell transplantation for multiple sclerosis. J Clin Invest (2014) 124:1168–72.10.1172/JCI71691
- Alexander T, Thiel A, Rosen O, Massenkeil G, Sattler A, Kohler S, et al. Depletion of autoreactive immunologic memory followed by autologous hematopoietic stem cell transplantation in patients with refractory SLE induces long-term remission through de novo generation of a juvenile and tolerant immune system. Blood (2009) 113:214–23.10.1182/blood-2008-07-168286
- Farge D, Henegar C, Carmagnat M, Daneshpouy M, Marjanovic Z, Rabian C, et al. Analysis of immune reconstitution after autologous bone marrow transplantation in systemic sclerosis. Arthritis Rheum (2005) 52:1555–63.10.1002/art.21036
- Jordan L. The problem with big data in translational medicine. A review of where we’ve been and the possibilities ahead. Appl Transl Genom (2015) 6:3–6.10.1016/j.atg.2015.07.005
- Capobianco M, Motuzova Y, Frau J, Cocco E, Mamusa E, Marrosu MG, et al. Natalizumab in aggressive multiple sclerosis after haematopoietic stem cell transplantation. Neurol Sci (2012) 33:863–7.10.1007/s10072-011-0848-1
- D’Addio F, Valderrama Vasquez A, Ben Nasr M, Franek E, Zhu D, Li L, et al. Autologous nonmyeloablative hematopoietic stem cell transplantation in new-onset type 1 diabetes: a multicenter analysis. Diabetes (2014) 63:3041–6.10.2337/db14-0295
- Asare AL, Carey VJ, Rotrosen D, Nepom GT. Clinical trial data access: opening doors with TrialShare. J Allergy Clin Immunol (2016) 138:724–6.10.1016/j.jaci.2016.05.034
- R Core Team. R: A Language and Environment for Statistical Computing R Foundation for Statistical Computing. Vienna, Austria: R Foundation for Statistical Computing; (2017). Available from: .
Source: PubMed