CTL-promoting effects of CD40 stimulation outweigh B cell-stimulatory effects resulting in B cell elimination and disease improvement in a murine model of lupus.
CD40/CD40L signaling promotes both B cell and CTL responses in vivo, the latter being beneficial in tumor models. Because CTL may also limit autoreactive B cell expansion in lupus, we asked whether an agonist CD40 mAb would exacerbate lupus due to B cell stimulation or would improve lupus due to CTL promotion. These studies used an induced model of lupus, the parent-into-F1 model in which transfer of DBA/2 splenocytes into B6D2F1 mice induces chronic lupus-like graft-vs-host disease (GVHD). Although agonist CD40 mAb treatment of DBA-->F1 mice initially exacerbated B cell expansion, it also strongly promoted donor CD8 T cell engraftment and cytolytic activity such that by 10 days host B cells were eliminated consistent with an accelerated acute GVHD. CD40 stimulation bypassed the requirement for CD4 T cell help for CD8 CTL possibly by licensing dendritic cells (DC) as shown by the following: 1) greater initial activation of donor CD8 T cells, but not CD4 T cells; 2) earlier activation of host DC; 3) host DC expansion that was CD8 dependent and CD4 independent; and 4) induction of acute GVHD using CD4-depleted purified DBA CD8+ T cells. A single dose of CD40 mAb improved lupus-like renal disease at 12 wk, but may not suffice for longer periods consistent with a need for continuing CD8 CTL surveillance. These results demonstrate that in the setting of lupus-like CD4 T cell-driven B cell hyperactivity, CTL promotion is both feasible and beneficial and the CTL-promoting properties of CD40 stimulation outweigh the B cell-stimulatory properties.
Pathology Department, Uniformed Services University of Health Sciences, Bethesda, MD 20814, USA.
Roman
R
Puliaev
Irina
I
Puliaeva
Lisbeth A
LA
Welniak
Abigail E
AE
Ryan
Mark
M
Haas
William J
WJ
Murphy
Charles S
CS
Via
D000818:Animals; D000911:Antibodies, Monoclonal / Q000276:immunology / Q000627:therapeutic use; D001402:B-Lymphocytes / Q000276:immunology*; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology; D019013:CD40 Antigens / Q000819:agonists / Q000276:immunology*; D002478:Cells, Cultured; D003602:Cytotoxicity, Immunologic / Q000276:immunology; D003713:Dendritic Cells / Q000276:immunology; D004195:Disease Models, Animal; D006086:Graft vs Host Disease / Q000188:drug therapy / Q000276:immunology; D008180:Lupus Erythematosus, Systemic / Q000276:immunology*; D008213:Lymphocyte Activation / Q000276:immunology; D008297:Male; D051379:Mice; D010641:Phenotype; D013602:T-Lymphocytes, Cytotoxic / Q000276:immunology*; D013997:Time Factors
D000911:Antibodies, Monoclonal; D019013:CD40 Antigens