Cytapheresis with a filter for selective removal of CD4+ T cells in experimental autoimmune encephalomyelitis

Abstract

Experimental autoimmune encephalomyelitis (EAE) is a major animal model of human multiple sclerosis (MS). CD4⁺ T cells are thought to play a pivotal role in the patho genesis of EAE and MS. In order to investigate the depletio n of CD4⁺ T cells from the systemic circulation as an effective strategy for the treatment of MS, we performed extracorporeal CD4⁺ T cell adsorption, using a filter to which anti-CD4⁺ antibody is immobilized as a ligand, in adoptively transferred EAE. Rats treated with CD4⁺ T cell removal filter (C D4RF) exhibited milder clinical signs of EAE and earlier recovery than those receiving sham treatment. Moreover, the thymic cells from EAE rats treated with C D4RF exhibited a suppressed proliferative response and IFN-g production to myelin basic protein. These results suggest that depletion of CD4⁺ T cells from the systemic circulation by extracorporeal treatment is a potentially useful strategy for treatment of acute phase and relapsing MS.

Keywords

autoimmunity C D4 cytapheresis experimental autoimmune encephalomyelitis (EA E)immunotherapy T cells

Get full access to this article

View all access options for this article.

References

McFarlin DE , McFarland HF. Multiple sclerosis . N Engl J Med 1982; 307: 1183-1188 .

Hafler DA , Weiner HL. T-cells in multiple sclerosis and inflammatory central nervous system diseases . Immunol Rev 1987; 100: 307-333 .

Noseworthy JH , Lucchinetti C , Rodriguez M , Weinshenker BG. Multiple sclerosis . N Engl J Med 2000; 243: 938-950 .

Raine CS. Analysis of autoimmune demyelination: its impact upon multiple sclerosis . Lab Invest 1984; 50: 608-635 .

Owens T , Sriram S. The immunology of multiple sclerosis and its animal model, experimental allergic encephalomyelitis . Neurol Clin 1995; 13: 51-73 .

Takenaka A , Kaneko K , Mori R , Itoyama Y. Adoptive transfer of experimental allergic encephalomyelitis with lectin-activated spleen cells . J Neurol Sci 1984; 66: 255-261 .

Vandenbark AA , Gill T , Offner H. A myelin basic protein-specific T lymphocyte line that mediates experimental auto-immune encephalomyelitis . J Immunol 1985; 135: 223-228 .

Xiao BG , Link H. Antigen-specific T cells in autoimmune diseases with a focus on multiple sclerosis and experimental allergic encephalomyelitis . Cell Mol Life Sci 1999; 56: 5-21 .

Sawcer S , Jones HB , Feakes R , Gray J , Smaldon N , Chataway J et al. A genome screen in multiple sclerosis reveals susceptibility loci on chromosome 6p21 and 17q22 . Nat Genet 1996; 13: 464-468 .

10.

Haines JL , Ter-Minassian M , Bazyk A , Gusella JF , Kim DJ , Terwedow H et al. A complete genomic screen for multiple sclerosis underscores a role for the major histocompatability complex. The Multiple Sclerosis Genetics Group . Nat Genet 1996; 13: 469-471 .

11.

Ebers GC , Kukay K , Bulman DE , Sadovnick AD , Rice G , Anderson C et al. A full genome search in multiple sclerosis . Nat Genet 1996; 13: 472-476 .

12.

Sriram S , Solomon D , Rouse RV , Steinman L. identification of T cell subsets and B lymphocytes in mouse brain experimental allergic encephalitis lesions . J Immunol 1982; 129: 1649-1651 .

13.

Waldor MK , Sriram S , Hardy R , Herzenberg LA , Herzenberg LA , Lanier L et al. Reversal of experimental allergic encephalomyelitis with monoclonal antibody to a T-cell subset marker . Science 1985; 227: 415-417 .

14.

Traugott U , Reinherz EL , Raine CS. Multiple sclerosis: distribution of T cell subsets within active chronic lesions . Science 1983; 219: 308-310 .

15.

Pettinelli CB , McFarlin DE. Adoptive transfer of experimental allergic encephalomyelitis in SJL/J mice after in vitro activation of lymph node cells by myelin basic protein: requirement for Lyt 1+2-T lymphocytes . J Immunol 1981; 127: 1420-1423 .

16.

Edling AE , Choksi S , Huang Z , Korngold R. An organic CD4 inhibitor reduces the clinical and pathological symptoms of acute experimental allergic encephalomyelitis . J Autoimmun 2000; 18: 169-179 .

17.

Waldmann H. Manipulation of T-cell responses with monoclonal antibodies . Annu Rev Immunol 1989; 7: 407-444 .

18.

O’Neill JK , Baker D , Davison AN , Allen SJ , Butter C , Waldmann H et al. Control of immune-mediated disease of the central nervous system with monoclonal (CD4-specific) antibodies . J Neuroimmunol 1993; 45: 1-14 .

19.

Brostoff SW , Mason DW. Experimental allergic encephalomyelitis: successful treatment in vivo with a monoclonal antibody that recognizes T helper cells . J Immunol 1984; 133: 1938-1942 .

20.

Hafler DA , Ritz J , Schlossman SF , Weiner HL. Anti-CD4 and anti-CD2 monoclonal antibody infusions in subjects with multiple sclerosis. Immunosuppressive effects and human anti-mouse responses . J Immunol 1988; 141: 131-138 .

21.

Goldberg D , Morel P , Chatenoud L , Boitard C , Menkes CJ , Bertoye PH et al. Immunological effects of high dose administration of anti-CD4 antibody in rheumatoid arthritis patients . J Autoimmun 1991; 4: 617-630 .

22.

Hiepe F , Volk HD , Apostoloff E , von Baehr R , Emmrich F. Treatment of severe systemic lupus erythematosus with anti-CD4 monoclonal antibody . Lancet 1991; 338: 1529-1530 .

23.

Reiter C , Kakavand B , Rieber EP , Schattenkirchner M , Riethmuller G , Kruger K. Treatment of rheumatoid arthritis with monoclonal CD4 antibody M-T151. Clinical results and immunopharmacologic effects in an open study, including repeated administration . Arthritis Rheum 1991; 34: 525-536 .

24.

Lindsey JW , Hodgkinson S , Mehta R , Mitchell D , Enzmann D , Steinman L. Repeated treatment with chimeric anti-CD4 antibody in multiple sclerosis . Ann Neurol 1994; 36: 183-189 .

25.

van Oosten BW , Lai M , Hodgkinson S , Barkhof F , Miller DH , Moseley IF et al. Treatment of multiple sclerosis with the monoclonal anti-CD4 antibody cM-T412: results of a randomized, double-blind, placebo-controlled, MR-monitored phase II trial . Neurology 1997; 49: 351-357 .

26.

Rose J , Klein H , Greenstein J , McFarlin D , Gerber L , McFarland H. Lymphocytapheresis in chronic progressive multiple sclerosis: results of a preliminary trial . Ann Neurol 1983; 14: 593-594 .

27.

Hauser SL , Fosburg M , Kevy SV , Weiner HL. Lymphocytapheresis in chronic progressive multiple sclerosis: immunologic and clinical effects . Neurology 1984; 34: 922-926 .

28.

Matsuo H , Ichinose K , Ohtsuru I , Fujishita S , Onodera H , Suematsu J et al. Treatment of experimental allergic encephalomyelitis by selective removal of CD4+ T cells . Ther Apher 1997; 1: 165-168 .

29.

Onodera H , Abe Y , Yoshida M , Yamawaki N , Yamashita Y , Matsuo H et al. A new device for selective removal of CD4+ T cells . Ther Apher 1998; 2: 37-42 .

30.

Ahn M , Kang J , Lee Y , Riu K , Kim Y , Jee Y et al. Pertussis toxin-induced hyperacute autoimmune encephalomyelitis in Lewis rats is correlated with increased expression of inducible nitric oxide synthase and tumor necrosis factor alpha . Neurosci Lett 2001; 308: 41-44 .

31.

Naparstek Y , Holoshitz J , Eisenstein S , Reshef T , Rappaport S , Chemke J et al. Effector T lymphocyte line cells migrate to the thymus and persist there . Nature 1982; 300: 262-264 .

32.

Naparstek Y , Ben-Nun A , Holoshitz J , Reshef T , Frenkel A , Rosenberg M et al. T lymphocyte lines producing or vaccinating against autoimmune encephalomyelitis (EAE). Functional activation induces peanut agglutinin receptors and accumulation in the brain and thymus of line cells . Eur J Immunol 1983; 13: 418-423 .

33.

Wucherpfennig KW , Zhang J , Witek C , Matsui M , Modabber Y , Ota K et al. Clonal expansion and persistence of human T cells specific for an immunodominant myelin basic protein peptide . J Immunol 1994; 152: 5581-5592 .

34.

Illes Z , Kondo T , Yokoyama K , Ohashi T , Tabira T , Yamamura T. identification of autoimmune T cells among in vivo expanded CD25+ T cells in multiple sclerosis . J Immunol 1999; 162: 1811-1817 .

35.

Cannella B , Raine CS. The adhesion molecule and cytokine profile of multiple sclerosis lesions . Ann Neurol 1995; 37: 424-435 .

36.

Mosmann TR , Cherwinski H , Bond MW , Giedlin MA , Coffman RL. Two types of murine helper T cell clone. I. Definition according to profiles of lymphokine activities and secreted proteins . J Immunol 1986; 136: 2348-2357 .

37.

Babbe H , Roers A , Waisman A , Lassmann H , Goebels N , Hohlfeld R et al. Clonal expansions of CD8(+) T cells dominate the T cell infiltrate in active multiple sclerosis lesions as shown by micromanipulation and single cell polymerase chain reaction . J Exp Med 2000; 192: 393-404 .

38.

Huseby ES , Liggitt D , Brabb T , Schnabel B , Ohlen C , Goverman J. A pathogenic role for myelin-specific CD8(+) T cells in a model for multiple sclerosis . J Exp Med 2001; 194: 669-676 .

39.

Neumann H , Medana IM , Bauer J , Lassmann H. Cytotoxic T lymphocytes in autoimmune and degenerative CNS diseases . Trends Neurosci 2002; 25: 313-319 .