Regulatory T cells and their potential for tolerance induction in haemophilia A patients

A. Schmidt; C. Königs; ABIRISK consortium; on behalf of

doi:10.1055/s-0037-1616867

Hämostaseologie, Table of Contents

Hamostaseologie 2016; 36(S 02): S5-S12
DOI: 10.1055/s-0037-1616867

Review

Schattauer GmbH

Regulatory T cells and their potential for tolerance induction in haemophilia A patients

Das Potenzial regulatorischer T-Zellen zur Toleranz induktion bei Hämophilie-A-Patienten

A. Schmidt

¹Molecular Haemostasis and Immunodeficiency, Department of Paediatrics, University Hospital Frankfurt, Goethe University, Frankfurt am Main, Germany

,

C. Königs

¹Molecular Haemostasis and Immunodeficiency, Department of Paediatrics, University Hospital Frankfurt, Goethe University, Frankfurt am Main, Germany

,

ABIRISK consortium

› Author Affiliations

Abstract

Summary

FVIII inhibitors still are the major concern in treatment of haemophilia A patients by FVIII replacement therapy. Immune tolerance induction to reverse inhibitor formation fails in about 30% of treated patients. These patients face increased morbidity and mortality producing a need for new therapy strategies in the treatment of FVIII inhibitor-positive patients. Regulatory T cells are important modulators of the immune response and are also involved in the immune response to FVIII in haemophilia A patients. Additionally, regulatory T cells have been shown to play a role in tolerance induction induced by multiple experimental treatment regimes.

This review summarises the current knowledge on the role of regulatory T cells in the immune response to FVIII and tolerance induction strategies. Additionally, possible ways to engineer regulatory T cells as therapeutic agent in haemophilia A and current challenges of regulatory T cell therapies are discussed.

Zusammenfassung

FVIII-Inhibitoren stellen das größte Risiko bei der FVIII-Ersatztherapie dar. Die Immuntoleranzinduktion scheitert in etwa 30% der Patienten, was in einer erhöhten Morbidität und Mortalität resultiert. Aus diesem Grund ist die Entwicklung neuer Therapien für FVIII-Inhibitor-positive Patienten von großer Bedeutung. Regulatorische T-Zellen sind wichtige Modulatoren der Immunantwort und auch an der FVIII-spezifischen Immunreaktion von Hämophilie-A-Patienten beteiligt. Außerdem konnte in verschiedenen experimentellen Therapien eine Beteiligung von regulatorischen T-Zellen an der Toleranzinduktion gezeigt werden.

Diese Übersichtsarbeit fasst das aktuelle Wissen über die Beteiligung regulatorischer T-Zellen an FVIII-spezifischen Immunantworten und Strategien zur Toleranzinduktion zusammen. Des Weiteren werden Möglichkeiten zur Modifikation von regulatorischen T-Zellen für den Einsatz als Therapeutika und aktuelle Herausforderungen dieser Zell-basierten Therapien diskutiert.

Keywords

Häemophilia A - tolerance - regulatory T cells

Keywords

Hämophilie A - Toleranz - regulatorische T-Zellen

Full Text

References

References
1 Andolfi G, Fousteri G. et al. Enforced IL-10 expression confers type 1 regulatory T cell (Tr1) phenotype and function to human CD4(+) T cells. Mol Ther 2012; 20: 1778-1790.
2 Astermark J, Oldenburg J. et al. Polymorphisms in the IL10 but not in the IL1beta and IL4 genes are associated with inhibitor development in patients with hemophilia A. Blood 2006; 107: 3167-3172.
3 Bacchetta R, Bigler M. et al. High levels of interleukin 10 production in vivo are associated with tolerance in SCID patients transplanted with HLA mismatched hematopoietic stem cells. J Exp Med 1994; 179: 493-502.
4 Barthlott T, Kassiotis G, Stockinger B. T cell regulation as a side effect of homeostasis and competition. J Exp Med 2003; 197: 451-460.
5 Blat D, Zigmond E. et al. Suppression of murine colitis and its associated cancer by carcinoembryonic antigen-specific regulatory T cells. Mol Ther 2014; 22: 1018-1028.
6 Boyman O, Kovar M. et al. Selective stimulation of T cell subsets with antibody-cytokine immune complexes. Science 2006; 311: 1924-1927.
7 Bray GL, Kroner BL. et al. Loss of high-responder inhibitors in patients with severe hemophilia A and human immunodeficiency virus type 1 infection: a report from the Multi-Center Hemophilia Cohort Study. Am J Hematol 1993; 42: 375-379.
8 Chai JG, Xue SA. et al. Regulatory T cells, derived from naïve CD4+CD25– T cells by in vitro Foxp3 gene transfer, can induce transplantation tolerance. Transplantation. 2005; 79: 1310-1316.
9 Chaves DG, Velloso-Rodrigues C. et al. A shift towards a T cell cytokine deficiency along with an anti-inflammatory/regulatory microenvironment may enable the synthesis of anti-FVIII inhibitors in haemophilia A patients. Clin Exp Immunol 2010; 162: 425-437.
10 Chen TC, Cobbold SP. et al. Generation of anergic and regulatory T cells following prolonged exposure to a harmless antigen. J Immunol 2004; 172: 5900-5907.
11 Chen Y, Kuchroo VK. et al. Regulatory T cell clones induced by oral tolerance: suppression of autoimmune encephalomyelitis. Science 1994; 265: 1237-1240.
12 Cousens LP, Tassone R. et al. Tregitope update: mechanism of action parallels IVIg. Autoimmun Rev 2013; 12: 436-443.
13 De Groot AS, Moise L. et al. Activation of natural regulatory T cells by IgG Fc-derived peptide Tregitopes“. Blood 2008; 112: 3303-3311.
14 Dixon FJ, Mauer PH. Immunologic unresponsiveness induced by protein antigens. J Exp Med 1955; 101: 245-257.
15 El-Asrar M, Hamed A. et al. Assessment of the frequency of regulatory T cells (CD4+CD25+CD127-) in children with hemophilia A: relation to factor VIII inhibitors and disease severity. Blood Coagul Fibrinolysis 2016; 27: 42-46.
16 Ephrem A, Chamat S. et al. Expansion of CD4+CD25+ regulatory T cells by intravenous immunoglobulin: a critical factor in controlling experimental autoimmune encephalomyelitis. Blood 2008; 111: 715-722.
17 Ettinger RA, James EA. et al. Lineages of human T-cell clones, including T helper 17/T helper 1 cells, isolated at different stages of anti-factor VIII immune responses. Blood 2009; 114: 1423-1428.
18 Fransson M, Piras E. et al. CAR/FoxP3-engineered T regulatory cells target the CNS and suppress EAE upon intranasal delivery. J Neuroinflammation 2012; 9: 112.
19 Furie B, Furie BC. Molecular basis of hemophilia. Semin Hematol 1990; 27: 270-285.
20 Gershon RK, Cohen P. et al. Suppressor T cells. J Immunol 1972; 108: 586-590.
21 Groux H, O’Garra A. et al. A CD4+ T-cell subset inhibits antigen-specific T-cell responses and prevents colitis. Nature 1997; 389: 737-742.
22 Gupta N, Culina S. et al. Regulation of immune responses to protein therapeutics by transplacental induction of T cell tolerance. Sci Transl Med 2015; 7: 275ra21.
23 Hausl C, Ahmad RU. et al. High-dose factor VIII inhibits factor VIII-specific memory B cells in hemophilia A with factor VIII inhibitors. Blood 2005; 106: 3415-3422.
24 Hay CR, Dimichele DM, Study IIT. The principal results of the International Immune Tolerance Study: a randomized dose comparison. Blood 2012; 119: 1335-1344.
25 Hori S, Nomura T, Sakaguchi S. Control of regulatory T cell development by the transcription factor Foxp3. Science 2003; 299: 1057-1061.
26 Hu G, Guo D. et al. Cytokine production by CD4+ T cells specific for coagulation factor VIII in healthy subjects and haemophilia A patients. Thromb Haemost 2007; 97: 788-794.
27 Huang H, Dawicki W. et al. Tolerogenic dendritic cells induce CD4+CD25hiFoxp3+ regulatory T cell differentiation from CD4+CD25-/loFoxp3– effector T cells. J Immunol 2010; 185: 5003-5010.
28 Huang H, Ma Y. et al. Comparison of induced versus natural regulatory T cells of the same TCR specificity for induction of tolerance to an environmental antigen. J Immunol 2013; 191: 1136-1143.
29 Iorio A, Halimeh S. et al. Rate of inhibitor development in previously untreated hemophilia A patients treated with plasma-derived or recombinant factor VIII concentrates: a systematic review. J Thromb Haemost 2010; 8: 1256-1265.
30 Jacquemin MG, Desqueper BG. et al. Mechanism and kinetics of factor VIII inactivation: study with an IgG4 monoclonal antibody derived from a hemophilia A patient with inhibitor. Blood 1998; 92: 496-506.
31 James EA, Kwok WW. et al. T-cell responses over time in a mild hemophilia A inhibitor subject: epitope identification and transient immunogenicity of the corresponding self-peptide. J Thromb Hae-most 2007; 5: 2399-2407.
32 Kamaté C, Lenting PJ. et al. Depletion of CD4+/CD25high regulatory T cells may enhance or uncover factor VIII-specific T-cell responses in healthy individuals. J Thromb Haemost 2007; 5: 611-613.
33 Kim YC, Bhairavabhotla R. et al. Oligodeoxynucleotides stabilize Helios-expressing Foxp3+ human T regulatory cells during in vitro expansion. Blood 2012; 119: 2810-2818.
34 Kim YC, Zhang AH. et al. Engineered antigen-specific human regulatory T cells: immunosuppression of FVIII-specific T- and B-cell responses. Blood 2015; 125: 1107-1115.
35 Krishnamoorthy S, Liu T. et al. Recombinant factor VIII Fc (rFVIIIFc) fusion protein reduces immunogenicity and induces tolerance in hemophilia A mice. Cell Immunol 2016; 301: 30-39.
36 Lécart S, Morel F. et al. IL-22, in contrast to IL-10, does not induce Ig production, due to absence of a functional IL-22 receptor on activated human B cells. Int Immunol 2002; 14: 1351-1356.
37 Lei TC, Scott DW. Induction of tolerance to factor VIII inhibitors by gene therapy with immuno-dominant A2 and C2 domains presented by B cells as Ig fusion proteins. Blood 2005; 105: 4865-4870.
38 Lindley S, Dayan CM. et al. Defective suppressor function in CD4(+)CD25(+) T-cells from patients with type 1 diabetes. Diabetes 2005; 54: 92-99.
39 Liu CL, Ye P. et al. Long-term tolerance to factor VIII is achieved by administration of IL-2/IL-2mAb complexes and low dosages of factor VIII. J Thromb Haemost 2014; 12: 921-931.
40 Liu CL, Ye P. et al. In vivo expansion of regulatory T cells with IL-2/IL-2 mAb complexes prevents anti-factor VIII immune responses in hemophilia A mice treated with factor VIII plasmid-mediated gene therapy. Mol Ther 2009; 19: 1511-1520.
41 Liu W, Putnam A. et al. CD127 expression inversely correlates with FoxP3 and suppressive function of human CD4+ T reg cells. J Exp Med 2006; 203: 1701-1711.
42 Madoiwa S, Yamauchi T. et al. Induction of factor VIII-specific unresponsiveness by intrathymic factor VIII injection in murine hemophilia A. J Thromb Haemost 2009; 7: 811-824.
43 Maldonado RA, LaMothe RA. et al. Polymeric synthetic nanoparticles for the induction of antigen-specific immunological tolerance. Proc Natl Acad Sci USA 2015; 112: E156-E165.
44 Malek TR, Bayer AL. Tolerance, not immunity, crucially depends on IL-2. Nat Rev Immunol 2004; 4: 665-674.
45 Mantel PY, Kuipers H. et al. GATA3-driven Th2 responses inhibit TGF-beta1-induced FOXP3 expression and the formation of regulatory T cells. PLoS Biol 2007; 5: e329.
46 Matino D, Gargaro M. et al. IDO1 suppresses inhibitor development in hemophilia A treated with factor VIII. J Clin Invest 2015; 125: 3766-3781.
47 Matsui H, Shibata M. et al. A murine model for induction of long-term immunologic tolerance to factor VIII does not require persistent detectable levels of plasma factor VIII and involves contributions from Foxp3+ T regulatory cells. Blood 2009; 114: 677-685.
48 Miao CH, Harmeling BR. et al. CD4+FOXP3+ regulatory T cells confer long-term regulation of factor VIII-specific immune responses in plasmid-mediated gene therapy-treated hemophilia mice. Blood 2009; 114: 4034-4044.
49 Moghimi B, Sack BK. et al. Induction of tolerance to factor VIII by transient co-administration with rapamycin. J Thromb Haemost 2011; 9: 1524-1533.
50 Morgan RA, Chinnasamy N. et al. Cancer regression and neurological toxicity following anti-MAGE-A3 TCR gene therapy. J Immunother 2013; 36: 133-151.
51 Naumann A, Scherger AK. et al. Selection and characterisation of FVIII-specific single chain variable fragments. Hämostaseologie 2013; 33 (Suppl. 01) S39-S45.
52 Noyan F, Lee YS. et al. Isolation of human antigen-specific regulatory T cells with high suppressive function. Eur J Immunol 2014; 44: 2592-2602.
53 Oliveira VG, Agua-Doce A. et al. Adjuvant facilitates tolerance induction to factor VIII in hemophilic mice through a Foxp3-independent mechanism that relies on IL-10. Blood 2013; 121: 3936-3945.
54 Peng B, Ye P. et al. Anti-CD3 antibodies modulate anti-factor VIII immune responses in hemophilia A mice after factor VIII plasmid-mediated gene therapy. Blood 2009; 114: 4373-4382.
55 Ramakrishnan R, Davidowitz A, Balu-Iyer SV. Exposure of FVIII in the presence of phosphatidyl serine reduces generation of memory B-cells and induces regulatory T-cell-mediated hyporesponsiveness in hemophilia A mice. J Pharm Sci 2015; 104: 2451-2456.
56 Ramani K, Miclea RD. et al. Phosphatidylserine containing liposomes reduce immunogenicity of recombinant human factor VIII (rFVIII) in a murine model of hemophilia A. J Pharm Sci 2008; 97: 1386-1398.
57 Reding MT, Okita DK. et al. Human CD4+ T-cell epitope repertoire on the C2 domain of coagulation factor VIII. J Thromb Haemost 2003; 1: 1777-1784.
58 Reding MT, Okita DK. et al. Epitope repertoire of human CD4(+) T cells on the A3 domain of coagulation factor VIII. J Thromb Haemost 2004; 2: 1385-1394.
59 Sakaguchi S, Sakaguchi N. et al. Immunologic self-tolerance maintained by activated T cells expressing IL-2 receptor alpha-chains (CD25). Breakdown of a single mechanism of self-tolerance causes various autoimmune diseases. J Immunol 1995; 155: 1151-1164.
60 Sarkar D, Biswas M. et al. Ex vivo expanded autologous polyclonal regulatory T cells suppress inhibitor formation in hemophilia. Mol Ther Methods Clin Dev 2014; 1: 14030.
61 Schmid DA, Irving MB. et al. Evidence for a TCR affinity threshold delimiting maximal CD8 T cell function. J Immunol 2010; 184: 4936-4946.
62 Seder RA, Marth T. et al. Factors involved in the differentiation of TGF-beta-producing cells from naive CD4+ T cells: IL-4 and IFN-gamma have opposing effects, while TGF-beta positively regulates its own production. J Immunol 1998; 160: 5719-5728.
63 Shao H, Zhang W. et al. TCR mispairing in genetically modified T cells was detected by fluorescence resonance energy transfer. Mol Biol Rep 2010; 37: 3951-3956.
64 Sherman A, Su J. et al. Suppression of inhibitor formation against factor VIII in hemophilia A mice by oral delivery of antigens bioencapsulated in plant cells. Blood 2014; 124: 1959-1968.
65 Silveira AC, Santana MA. et al. The IL-10 polarized cytokine pattern in innate and adaptive immunity cells contribute to the development of FVIII inhibitors. BMC Hematol 2015; 15: 1.
66 Singer ST, Addiego JE. et al. T lymphocyte proliferative responses induced by recombinant factor VIII in hemophilia A patients with inhibitors. Thromb Haemost 1996; 76: 17-22.
67 Skupsky J, Zhang AH. et al. B-cell-delivered gene therapy induces functional T regulatory cells and leads to a loss of antigen-specific effector cells. Mol Ther 2010; 18: 1527-1535.
68 Thornton AM, Korty PE. et al. Expression of Helios, an Ikaros transcription factor family member, differentiates thymic-derived from peripherally induced Foxp3+ T regulatory cells. J Immunol 2010; 184: 3433-3441.
69 Tran DQ, Andersson J. et al. Selective expression of latency-associated peptide (LAP) and IL-1 receptor type I/II (CD121a/CD121b) on activated human FOXP3+ regulatory T cells allows for their purification from expansion cultures. Blood 2009; 113: 5125-5133.
70 Tran DQ, Andersson J. et al. GARP (LRRC32) is essential for the surface expression of latent TGF-beta on platelets and activated FOXP3+ regulatory T cells. Proc Natl Acad Sci USA 2009; 106: 13445-13450.
71 Tsuji NM, Kosaka A. Oral tolerance: intestinal homeostasis and antigen-specific regulatory T cells. Trends Immunol 2008; 29: 532-540.
72 Wang X, Su J. et al. Plant-based oral tolerance to hemophilia therapy employs a complex immune regulatory response including LAP+CD4+ T cells. Blood 2015; 125: 2418-2427.
73 Webster KE, Walters S. et al. In vivo expansion of T reg cells with IL-2-mAb complexes: induction of resistance to EAE and long-term acceptance of islet allografts without immunosuppression. J Exp Med 2009; 206: 751-760.
74 Wolf AM, Wolf D. et al. Increase of regulatory T cells in the peripheral blood of cancer patients. Clin Cancer Res 2003; 9: 606-612.
75 Zhang AH, Rossi RJ. et al. Tolerogenic nanoparticles to induce immunologic tolerance: Prevention and reversal of FVIII inhibitor formation. Cell Immunol 2015; 301: 74-81.