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CTL-Promoting Effects of CD40 Stimulation Outweigh B Cell-Stimulatory Effects Resulting in B Cell Elimination and Disease Improvement in a Murine Model of Lupus¹

Roman Puliaev^*,, Irina Puliaeva^*,, Lisbeth A. Welniak, Abigail E. Ryan^*,, Mark Haas, William J. Murphy and Charles S. Via^2,*,

^* Pathology Department, Uniformed Services University of Health Sciences, Bethesda, MD 20814; Research Service, Baltimore Veterans Affairs Medical Center, and Division of Rheumatology and Clinical Immunology, University of Maryland School of Medicine, Baltimore, MD 21201; Department of Microbiology and Immunology, University of Nevada School of Medicine, Reno, NV 89557; and Department of Pathology, Johns Hopkins University School of Medicine, Baltimore, MD 21287

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 DBAF₁ 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.

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ This work was supported by National Institutes of Health Grants RO1 AI047466 (to C.S.V.) and RO1 CA95572 (to W.M.).

² Address correspondence and reprint requests to Dr. Charles S. Via, Room B3-100, Department of Pathology, Uniformed Services University of Health Sciences, 4301 Jones Bridge Road, Bethesda, MD 20814. E-mail address: cvia{at}usuhs.mil

³ Abbreviations used in this paper: pfp, perforin; DC, dendritic cell; FasL, Fas ligand; GN, glomerulonephritis; GVHD, graft-vs-host disease; IVCCA, in vivo cytokine capture assay; PF₁, parent-into-F₁.