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Inhibition of a secondary human alloimmune response via the soluble active component of CD154 (CD40L) in severe combined immune‐deficient mice engrafted with human lymphocytes
Author(s) -
Lazarus A.H.,
Crow A.R,
Freedman J.,
Blanchette V.,
Hannach B.
Publication year - 1999
Publication title -
transfusion
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.045
H-Index - 132
eISSN - 1537-2995
pISSN - 0041-1132
DOI - 10.1046/j.1537-2995.1999.39080818.x
Subject(s) - cd154 , immune system , cd40 , immunology , antigen , t cell , biology , human leukocyte antigen , in vitro , cytotoxic t cell , biochemistry
BACKGROUND: Alloimmunization requires a process known as co‐stimulation. An important co‐stimulatory pathway for most immune responses is mediated by the interaction of CD40 on antigen‐presenting cells with CD154 (CD40L) on host T cells. Blockade of this co‐stimulatory pathway simultaneous with exposure to challenge with HLA‐incompatible cells is hypothesized to inhibit alloimmunization. STUDY DESIGN AND METHODS: Severe combined immune‐deficient (SCID) mice were reconstituted with human peripheral blood lymphocytes (Hu‐PBL‐SCID mice) from a subject primed to HLA antigens and challenged with HLA‐incompatible lymphocytes. Mice were challenged in the presence or absence of an 18‐kDa soluble recombinant active form of human CD154 (18‐kDa CD154). Human IgG production, alloimmunization, and in vitro T‐cell responsiveness were assessed. RESULTS: There was no significant effect of 18‐kDa CD154 on human IgG levels in these mice, but it inhibited the development of HLA‐specific alloantibody in this model to five subsequent untreated white cell challenges. In vitro T‐cell proliferation in a mixed lymphocyte culture was also prevented by 18‐kDa CD154. CONCLUSION: The recombinant protein 18‐kDa CD154 inhibited the ability of the Hu‐PBL‐SCID mice to mount a secondary immune response to allostimulation. This implies that transfusion‐induced alloimmunization utilizes CD40‐CD154 co‐stimulation and that blockade of this pathway can inhibit T‐cell function and interfere with the development of alloimmunization.