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Depletion of CD 52‐positive cells inhibits the development of central nervous system autoimmune disease, but deletes an immune‐tolerance promoting CD 8 T‐cell population. Implications for secondary autoimmunity of alemtuzumab in multiple sclerosis
Author(s) -
Kutzleben Stephanie,
Pryce Gareth,
Giovani Gavin,
Baker David
Publication year - 2017
Publication title -
immunology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.297
H-Index - 133
eISSN - 1365-2567
pISSN - 0019-2805
DOI - 10.1111/imm.12696
Subject(s) - cd52 , alemtuzumab , immunology , immune system , cd8 , antigen , antibody , biology , monoclonal antibody , population , cd19 , t cell , lymphocyte , multiple sclerosis , medicine , environmental health
Summary The objective was to determine whether CD 52 lymphocyte depletion can act to promote immunological tolerance induction by way of intravenous antigen administration such that it could be used to either improve efficiency of multiple sclerosis ( MS ) inhibition or inhibit secondary autoimmunities that may occur following alemtuzumab use in MS . Relapsing experimental autoimmune encephalomyelitis was induced in ABH mice and immune cell depletion was therapeutically applied using mouse CD 52 or CD 4 (in conjunction with CD 8 or CD 20) depleting monoclonal antibodies. Immunological unresponsiveness was then subsequently induced using intravenous central nervous system antigens and responses were assessed clinically. A dose–response of CD 4 monoclonal antibody depletion indicated that the 60–70% functional CD 4 T‐cell depletion achieved in perceived failed trials in MS was perhaps too low to even stop disease in animals. However, more marked (~75–90%) physical depletion of CD 4 T cells by CD 4 and CD 52 depleting antibodies inhibited relapsing disease. Surprisingly, in contrast to CD 4 depletion, CD 52 depletion blocked robust immunological unresponsiveness through a mechanism involving CD 8 T cells. Although efficacy was related to the level of CD 4 T‐cell depletion, the observations that CD 52 depletion of CD 19 B cells was less marked in lymphoid organs than in the blood provides a rationale for the rapid B‐cell hyper‐repopulation that occurs following alemtuzumab administration in MS . That B cells repopulate in the relative absence of T‐cell regulatory mechanisms that promote immune tolerance may account for the secondary B‐cell autoimmunities, which occur following alemtuzumab treatment of MS .