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.
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.


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.


CONCLUSIONS
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.
Lazarus
A H
AH
Department of Immunohematology, St. Michael's Hospital, University of Toronto, Ontario, Canada. lazarusa@smh.toronto.on.ca
Crow
A R
AR
Freedman
J
J
Blanchette
V
V
Hannach
B
B
D000818:Animals; D000917:Antibody Formation; D001402:B-Lymphocytes / Q000276:immunology / Q000378:metabolism; D023201:CD40 Ligand; D005260:Female; D006086:Graft vs Host Disease / Q000276:immunology; D006801:Humans; D007114:Immunization; D007074:Immunoglobulin G / Q000378:metabolism; D007075:Immunoglobulin M / Q000378:metabolism; D007156:Immunologic Memory; D007518:Isoantibodies / Q000276:immunology*; D007519:Isoantigens / Q000276:immunology*; D008213:Lymphocyte Activation; D017710:Lymphocyte Transfusion; D008562:Membrane Glycoproteins / Q000276:immunology*; D051379:Mice; D016513:Mice, SCID; D011994:Recombinant Proteins / Q000276:immunology; D014181:Transplantation Immunology
D007074:Immunoglobulin G; D007075:Immunoglobulin M; D007518:Isoantibodies; D007519:Isoantigens; D008562:Membrane Glycoproteins; D011994:Recombinant Proteins; D023201:CD40 Ligand