Intact active bone transplantation synergizes with anti-CD40 ligand therapy to induce B cell tolerance.
Blockade of T cell costimulatory pathways can result in the prolongation of allograft survival through the suppression of Th1 responses; however, late allograft rejection is usually accompanied by an emerging allograft-specific humoral response. We have recently determined that intact active bone (IAB) fragments transplanted under the kidney capsule can synergize with transient anti-CD40 ligand (CD40L) treatment to induce robust donor-specific allograft tolerance and suppress the alloantibody response. In this study, we take advantage of the ability of galactosyltransferase-deficient knockout (GT-Ko) mice to respond to the carbohydrate epitope, galactose-alpha1,3-galactose (Gal), to investigate whether IAB plus transient anti-CD40L therapy directly tolerize B cell responses. GT-Ko mice tolerized to Gal-expressing C3H hearts and IAB plus transient anti-CD40L therapy were challenged with pig kidney membranes that express high levels of Gal. The anti-Gal IgM and IgG responses were significantly suppressed in IAB-tolerant mice compared with controls, while the non-Gal anti-pig Ab responses were comparable. The anti-pig T cell cytokine response (IFN-gamma and IL-4) was comparable in IAB-tolerant and control mice. The tolerant state for the anti-Gal IgM response could be reversed with repeated immunization, whereas the tolerant state for the IgG response was robust and resisted repeated immunization. These observations provide an important proof-of-concept that adjunct therapies can synergize with anti-CD40L Abs to tolerize B cell responses independent of their effects on T cells. This model, which does not require mixed chimerism, provides a unique opportunity for investigating the mechanism of peripheral tolerance in a clinically relevant population of carbohydrate-specific B cells.
Yin
Dengping
D
Department of General Surgery, Rush Presbyterian Hospital, St. Luke's Medical Center, 1653 West Congress Parkway, Chicago, IL 60612, USA.
Ma
LianLi
L
Varghese
Anncy
A
Shen
JiKun
J
Chong
Anita S-F
AS
D000208:Acute Disease; D000818:Animals; D000911:Antibodies, Monoclonal / Q000627:therapeutic use*; D001402:B-Lymphocytes / Q000276:immunology*; D016025:Bone Transplantation / Q000276:immunology*; D023201:CD40 Ligand / Q000276:immunology*; D003131:Combined Modality Therapy / Q000379:methods; D016207:Cytokines / Q000096:biosynthesis; D004187:Disaccharides / Q000276:immunology; D006084:Graft Rejection / Q000276:immunology; D016027:Heart Transplantation / Q000276:immunology / Q000379:methods; D007075:Immunoglobulin M / Q000096:biosynthesis; D007165:Immunosuppression Therapy; D007518:Isoantibodies / Q000096:biosynthesis; D007668:Kidney; D051379:Mice; D008809:Mice, Inbred C3H; D008810:Mice, Inbred C57BL; D008811:Mice, Inbred DBA; D018345:Mice, Knockout; D051381:Rats; D011917:Rats, Inbred Lew; D013552:Swine; D013601:T-Lymphocytes / Q000276:immunology / Q000378:metabolism; D023001:Transplantation Tolerance; D014183:Transplantation, Heterologous / Q000276:immunology; D016042:Transplantation, Heterotopic / Q000276:immunology; D006022:beta-N-Acetylglucosaminylglycopeptide beta-1,4-Galactosyltransferase / Q000172:deficiency / Q000235:genetics
D000911:Antibodies, Monoclonal; D016207:Cytokines; D004187:Disaccharides; D007075:Immunoglobulin M; D007518:Isoantibodies; C055075:galactosyl-(1-3)galactose; D023201:CD40 Ligand; D006022:beta-N-Acetylglucosaminylglycopeptide beta-1,4-Galactosyltransferase