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Maintenance of Long-Lived Plasma Cells and Serological Memory Despite Mature and Memory B Cell Depletion during CD20 Immunotherapy in Mice¹

Department of Immunology, Duke University Medical Center, Durham, NC 27710

CD20 mAb-mediated B cell depletion is an effective treatment for B cell malignancies and some autoimmune diseases. However, the full effects of B cell depletion on natural, primary, and secondary Ab responses and the maintenance of Ag-specific serum Ig levels are largely unknown. The relationship between memory B cells, long-lived plasma cells, and long-lived humoral immunity also remains controversial. To address the roles of B cell subsets in the longevity of humoral responses, mature B cells were depleted in mice using CD20 mAb. Peritoneal B cell depletion reduced natural and Ag-induced IgM responses. Otherwise, CD20⁺ B cell depletion prevented humoral immune responses and class switching and depleted existing and adoptively transferred B cell memory. Nonetheless, B cell depletion did not affect serum Ig levels, Ag-specific Ab titers, or bone marrow Ab-secreting plasma cell numbers. Coblockade of LFA-1 and VLA-4 adhesion molecules temporarily depleted long-lived plasma cells from the bone marrow. CD20⁺ B cell depletion plus LFA-1/VLA-4 mAb treatment significantly prolonged Ag-specific plasma cell depletion from the bone marrow, with a significant decrease in Ag-specific serum IgG. Collectively, these results support previous claims that bone marrow plasma cells are intrinsically long-lived. Furthermore, these studies now demonstrate that mature and memory B cells are not required for maintaining bone marrow plasma cell numbers, but are required for repopulation of plasma cell-deficient bone marrow. Thereby, depleting mature and memory B cells does not have a dramatic negative effect on preexisting Ab levels.

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 study was supported by grants from the National Institutes of Health (CA105001, CA81776, CA96547, AI56363, AI24335, and AI67584), the Arthritis Foundation, and the Bill and Melinda Gates Foundation. K.M.H. is supported by a Special Fellow Award from the Leukemia and Lymphoma Society.

² D.J.D. and Y.H. contributed equally to this study and share first authorship.

³ Address correspondence and reprint requests to Dr. Thomas F. Tedder, Box 3010, Department of Immunology, Room 353, Jones Building, Research Drive, Duke University Medical Center, Durham, NC 27710. E-mail address: thomas.tedder{at}duke.edu

⁴ Abbreviations used in this paper: TI, T cell independent; ASC, Ab-secreting cell; KLH, keyhole limpet hemocyanin; NP-CGG, 4-hydroxy-3-nitrophenyl acetyl conjugated to chicken -globulin; TD, T cell dependent; TNP, 2,4,6-trinitrophenyl.

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