title: Lymphocyte homeostasis following therapeutic lymphocyte depletion in multiple sclerosis.
abstract: Following lymphocyte depletion, homeostatic mechanisms drive the reconstitution of lymphocytes. We prospectively studied this process in 16 patients for 1 year after a single pulse of treatment with Campath-1H, a humanised anti-CD52 monoclonal antibody. We observed two phases of lymphocyte reconstitution. In the first 6 months after treatment the precursor frequency and proliferation index of the patients' autologous mixed lymphocyte reaction increased; the depleted T cell pool was dominated by memory T cells, especially (CD4+)CD25high T cells, a putative regulatory phenotype; and there was a non-significant rise in peripheral mononuclear cell FoxP3 mRNA expression and fall in constitutive cytokine mRNA expression. In the later phase, from 6-to-12 months after Campath-1H, these changes reversed and there was a rise in ROG mRNA expression. However, total CD4+ numbers remained below 50% of pre-treatment levels at 12 months, perhaps reflecting a failure in homeostasis. This was not due to an impaired IL-7 response, as in rheumatoid arthritis, nor to a lack of IL-7 receptors, which are found on fewer human (CD4+)CD25high than naive cells. We speculate that CCL21 and IL-15 responses to lymphopaenia may be suboptimal in multiple sclerosis.
authors.affiliation: Department of Clinical Neurosciences, University of Cambridge, Cambridge, UK. alc1000@cam.ac.uk
authors.forename: Amanda L
authors.initials: AL
authors.lastname: Cox
authors.forename: Sara A J
authors.initials: SA
authors.lastname: Thompson
authors.forename: Joanne L
authors.initials: JL
authors.lastname: Jones
authors.forename: Vicki H
authors.initials: VH
authors.lastname: Robertson
authors.forename: Geoff
authors.initials: G
authors.lastname: Hale
authors.forename: Herman
authors.initials: H
authors.lastname: Waldmann
authors.forename: D Alastair S
authors.initials: DA
authors.lastname: Compston
authors.forename: Alasdair J
authors.initials: AJ
authors.lastname: Coles
mesh_terms: D000328:Adult; D000074323:Alemtuzumab; D000911:Antibodies, Monoclonal / Q000627:therapeutic use*; D061067:Antibodies, Monoclonal, Humanized; D000912:Antibodies, Neoplasm / Q000627:therapeutic use*; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology / Q000378:metabolism; D049109:Cell Proliferation; D002478:Cells, Cultured; D054421:Chemokine CCL21; D019742:Chemokines, CC / Q000097:blood; D005260:Female; D005786:Gene Expression Regulation / Q000276:immunology; D006706:Homeostasis / Q000235:genetics / Q000276:immunology*; D006801:Humans; D007156:Immunologic Memory / Q000235:genetics; D019409:Interleukin-15 / Q000097:blood; D015851:Interleukin-7 / Q000097:blood; D008212:Lymphocyte Depletion; D008297:Male; D008875:Middle Aged; D009103:Multiple Sclerosis / Q000276:immunology* / Q000628:therapy*; D011446:Prospective Studies; D015375:Receptors, Interleukin-2 / Q000378:metabolism; D020395:Receptors, Interleukin-7 / Q000096:biosynthesis / Q000235:genetics; D018417:Th1 Cells / Q000276:immunology* / Q000378:metabolism; D018418:Th2 Cells / Q000276:immunology* / Q000378:metabolism
chemical_list: D000911:Antibodies, Monoclonal; D061067:Antibodies, Monoclonal, Humanized; D000912:Antibodies, Neoplasm; C515478:CCL21 protein, human; D054421:Chemokine CCL21; D019742:Chemokines, CC; D019409:Interleukin-15; D015851:Interleukin-7; D015375:Receptors, Interleukin-2; D020395:Receptors, Interleukin-7; D000074323:Alemtuzumab