Biologic Agents in Crohn's Patients Reduce CD4 T Cells Activation and Are Inversely Related to Treg Cells

Crohn's disease (CD) is a chronic inflammatory disease with a complex interface of broad factors. There are two main treatments for Chron's disease: biological therapy and nonbiological therapy. Biological agent therapy (e.g., anti-TNF) is the most frequently prescribed treatment; however, it is not universally accessible. In fact, in Brazil, many patients are only given the option of receiving nonbiological therapy. This approach prolongs the subsequent clinical relapse; however, this procedure could be implicated in the immune response and enhance disease severity. Our purpose was to assess the effects of different treatments on CD4 T cells in a cohort of patients with Crohn's disease compared with healthy individuals. To examine the immune status in a Brazilian cohort, we analyzed CD4 T cells, activation status, cytokine production, and Treg cells in blood of Crohn's patients. Patients that underwent biological therapy can recover the percentage of CD4CD73 T cells, decrease the CD4 T cell activation/effector functions, and maintain the peripheral percentage of regulatory T cells. These results show that anti-TNF agents can improve CD4 T cell subsets, thereby inducing Crohn's patients to relapse and remission rates.

References

Schorer M, Lambert K, Rakebrandt N, Rost F, Kao K, Yermanos A . Rapid expansion of Treg cells protects from collateral colitis following a viral trigger. Nat Commun. 2020; 11(1):1522. PMC: 7090079. DOI: 10.1038/s41467-020-15309-6. View

Deaglio S, Dwyer K, Gao W, Friedman D, Usheva A, Erat A . Adenosine generation catalyzed by CD39 and CD73 expressed on regulatory T cells mediates immune suppression. J Exp Med. 2007; 204(6):1257-65. PMC: 2118603. DOI: 10.1084/jem.20062512. View

Tincati C, Bellistri G, Ancona G, Merlini E, Monforte A, Marchetti G . Role of in vitro stimulation with lipopolysaccharide on T-cell activation in HIV-infected antiretroviral-treated patients. Clin Dev Immunol. 2012; 2012:935425. PMC: 3287419. DOI: 10.1155/2012/935425. View

Ananthakrishnan A . Epidemiology and risk factors for IBD. Nat Rev Gastroenterol Hepatol. 2015; 12(4):205-17. DOI: 10.1038/nrgastro.2015.34. View

Miguel Luz Parente J, Coy C, Campelo V, Parente M, Costa L, da Silva R . Inflammatory bowel disease in an underdeveloped region of Northeastern Brazil. World J Gastroenterol. 2015; 21(4):1197-206. PMC: 4306164. DOI: 10.3748/wjg.v21.i4.1197. View

Cui G, Yuan A . A Systematic Review of Epidemiology and Risk Factors Associated With Chinese Inflammatory Bowel Disease. Front Med (Lausanne). 2018; 5:183. PMC: 6018203. DOI: 10.3389/fmed.2018.00183. View

Bishu S, El Zaatari M, Hayashi A, Hou G, Bowers N, Kinnucan J . CD4+ Tissue-resident Memory T Cells Expand and Are a Major Source of Mucosal Tumour Necrosis Factor α in Active Crohn's Disease. J Crohns Colitis. 2019; 13(7):905-915. PMC: 6939878. DOI: 10.1093/ecco-jcc/jjz010. View

Grundstrom J, Linton L, Thunberg S, Forsslund H, Janczewska I, Befrits R . Altered immunoregulatory profile during anti-tumour necrosis factor treatment of patients with inflammatory bowel disease. Clin Exp Immunol. 2012; 169(2):137-47. PMC: 3406373. DOI: 10.1111/j.1365-2249.2012.04600.x. View

Mascanfroni I, Yeste A, Vieira S, Burns E, Patel B, Sloma I . IL-27 acts on DCs to suppress the T cell response and autoimmunity by inducing expression of the immunoregulatory molecule CD39. Nat Immunol. 2013; 14(10):1054-63. PMC: 3964005. DOI: 10.1038/ni.2695. View

10.

Quaresma A, Kaplan G, Kotze P . The globalization of inflammatory bowel disease: the incidence and prevalence of inflammatory bowel disease in Brazil. Curr Opin Gastroenterol. 2019; 35(4):259-264. DOI: 10.1097/MOG.0000000000000534. View

11.

Mickael M, Bhaumik S, Basu R . Retinoid-Related Orphan Receptor RORγt in CD4 T-Cell-Mediated Intestinal Homeostasis and Inflammation. Am J Pathol. 2020; 190(10):1984-1999. DOI: 10.1016/j.ajpath.2020.07.010. View

12.

Song C, Zhang L, Wu X, Fu Y, Jiang Y, Shang H . CD4CD38 central memory T cells contribute to HIV persistence in HIV-infected individuals on long-term ART. J Transl Med. 2020; 18(1):95. PMC: 7038621. DOI: 10.1186/s12967-020-02245-8. View

13.

Kaplan G, Windsor J . The four epidemiological stages in the global evolution of inflammatory bowel disease. Nat Rev Gastroenterol Hepatol. 2020; 18(1):56-66. PMC: 7542092. DOI: 10.1038/s41575-020-00360-x. View

14.

Guidi L, Felice C, Procoli A, Bonanno G, Martinelli E, Marzo M . FOXP3⁺ T regulatory cell modifications in inflammatory bowel disease patients treated with anti-TNFα agents. Biomed Res Int. 2013; 2013:286368. PMC: 3766994. DOI: 10.1155/2013/286368. View

15.

Tippalagama R, Singhania A, Dubelko P, Arlehamn C, Crinklaw A, Pomaznoy M . HLA-DR Marks Recently Divided Antigen-Specific Effector CD4 T Cells in Active Tuberculosis Patients. J Immunol. 2021; 207(2):523-533. PMC: 8516689. DOI: 10.4049/jimmunol.2100011. View

16.

van de Donk N . Immunomodulatory effects of CD38-targeting antibodies. Immunol Lett. 2018; 199:16-22. DOI: 10.1016/j.imlet.2018.04.005. View

17.

Villegas-Ospina S, Aguilar-Jimenez W, Gonzalez S, Rugeles M . Vitamin D modulates the expression of HLA-DR and CD38 after in vitro activation of T-cells. Horm Mol Biol Clin Investig. 2017; 29(3):93-103. DOI: 10.1515/hmbci-2016-0037. View

18.

Robles R, Mukherjee S, Vuerich M, Xie A, Harshe R, Cowan P . Modulation of CD39 and Exogenous APT102 Correct Immune Dysfunction in Experimental Colitis and Crohn's Disease. J Crohns Colitis. 2019; 14(6):818-830. PMC: 7457187. DOI: 10.1093/ecco-jcc/jjz182. View

19.

Cosnes J, Gower-Rousseau C, Seksik P, Cortot A . Epidemiology and natural history of inflammatory bowel diseases. Gastroenterology. 2011; 140(6):1785-94. DOI: 10.1053/j.gastro.2011.01.055. View

20.

Sasson S, Slevin S, Cheung V, Nassiri I, Olsson-Brown A, Fryer E . Interferon-Gamma-Producing CD8 Tissue Resident Memory T Cells Are a Targetable Hallmark of Immune Checkpoint Inhibitor-Colitis. Gastroenterology. 2021; 161(4):1229-1244.e9. PMC: 8527886. DOI: 10.1053/j.gastro.2021.06.025. View