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.

Abstract

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.

• Authors: Roman Puliaev, Irina Puliaeva, Lisbeth A Welniak, Abigail E Ryan, Mark Haas, William J Murphy, Charles S Via
• Journal: Journal of immunology (Baltimore, Md. : 1950) (J Immunol) Vol. 181 Issue 1 Pg. 47-61 (Jul 01 2008) ISSN: 0022-1767 [Print] United States
• PMID: 18566369 (Publication Type: Journal Article, Research Support, N.I.H., Extramural)

Chemical References

• Antibodies, Monoclonal
• CD40 Antigens

Topics

• Animals
• Antibodies, Monoclonal (immunology, therapeutic use)
• B-Lymphocytes (immunology)
• CD4-Positive T-Lymphocytes (immunology)
• CD40 Antigens (agonists, immunology)
• Cells, Cultured
• Cytotoxicity, Immunologic (immunology)
• Dendritic Cells (immunology)
• Disease Models, Animal
• Graft vs Host Disease (drug therapy, immunology)
• Lupus Erythematosus, Systemic (immunology)
• Lymphocyte Activation (immunology)
• Male
• Mice
• Phenotype
• T-Lymphocytes, Cytotoxic (immunology)
• Time Factors