Inhibition of a secondary human alloimmune response via the soluble activecomponent of CD154 (CD40L) in severe combined immune-deficient mice engrafted with human lymphocytes

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 h ost T cells. Blockade of this costimulatory pathway simultaneous with expos ure to challenge with HLA-incompatible cells is hypothesized to inhibit all oimmunization. STUDY DESIGN AND METHODS: Severe combined immune-deficient (SCID) mice were reconstituted with human peripheral blood lymphocytes (Hu-PBL-SCID mice) f rom a subject primed to HLA antigens and challenged with HLA-incompatible l ymphocytes. Mice were challenged in the presence or absence of an 18-kDa so luble recombinant active form of human CD154 (18-kDa CD154). Human IgG prod uction, alloimmunization, and in vitro T-cell responsiveness were assessed. RESULTS: There was no significant effect of 18-kDa CD154 on human IgG level s in these mice, but it inhibited the development of HLA-specific alloantib ody in this model to five subsequent untreated white cell challenges. In vi tro T-cell proliferation in a mixed lymphocyte culture was also prevented b y 18-kDa GD154. CONCLUSION: The recombinant protein 18-kDa CD154 inhibited the ability of t he Hu-PBL-SCID mice to mount a secondary immune response to allostimulation . This implies that transfusion-induced alloimmunization utilizes CD40-CD15 4 co-stimulation and that blockade of this pathway can inhibit T-cell funct ion and interfere with the development of alloimmunization.