We found that transgenic (tg) mice stably expressing a bacterial artificial chromosome (BAC)-derived human complement receptor type 2 (CR2/CD21) gene demonstrate B cell specific hCR2 protein expression, normal B cell development and no changes in B cell subpopulations. To determine whether this BAC-encoded human CR2 (hCR2) can replace mouse CR2/CR1 in Cr2(-/-) mice and restore humoral immune responses to model foreign antigens (Ags), we generated hCR2(+/-)Cr2(-/-) tg mice and immunized them with sheep red blood cells (SRBC). We found that hCR2(+/-)Cr2(-/-) mice demonstrated anti-SRBC antibody (Ab) levels that were initially comparable to Cr2(-/-) mice after a single injection of the Ag, but then showed marked increases in anti-SRBC IgM and IgG1 levels after a second immunization. Identical results were found with a second model Ag, NP-Ficoll. To further confirm that this improvement in Ag-specific Ab production over Cr2(-/-) mice was indeed due to hCR2 expression, as well as to examine the effects of treating hCR2(+/-)Cr2(-/-) mice with an inhibitory anti-hCR2 monoclonal Ab (mAb) in vivo, we used mAb 171, an anti-hCR2 mAb that we have shown directly recognizes the C3d ligand binding site on hCR2. We first found that mAb 171 completely blocked hCR2-dependent co-activation of hCR2-tg B cells by anti-BCR/C3d complexes as measured in vitro by intracellular calcium influx. The i.p. injection of 1mg of mAb 171 was then found to induce for at least three weeks only partial loss of hCR2 surface expression, without modifying B and T cell numbers or the apparent activation status of the cells. Treatment of hCR2(+/-)Cr2(-/-) mice with mAb 171 also substantially suppressed the development of anti-SRBC and anti-NP Abs following immunization with Ags. The development of this model system should allow the study of the effects of manipulating hCR2 function in vivo with potential therapeutic compounds.

01 Apr 2007·BloodQ1 · MEDICINE

Mechanisms of regulation of CXCR4/SDF-1 (CXCL12)–dependent migration and homing in multiple myeloma

Q1 · MEDICINE

Article

Author: Roodman, G. David ; Ghobrial, Joanna M. ; Veilleux, Israel ; Jia, Xiaoying ; Hedin, Karen E. ; Witzig, Thomas E. ; Singha, Ujjal K. ; Côté, Daniel ; Leleu, Xavier ; Kimlinger, Teresa ; Pitsillides, Costas M. ; Ghobrial, Irene M. ; Lin, Charles P. ; Kung, Andrew L. ; Ngo, Hai ; Spencer, Joel A. ; Runnels, Judith ; Alsayed, Yazan ; Hideshima, Teru ; Timm, Michael ; Kumar, Ashok ; Anderson, Kenneth C. ; Lu, Ganwei

AbstractThe mechanisms by which multiple myeloma (MM) cells migrate and home to the bone marrow are not well understood. In this study, we sought to determine the effect of the chemokine SDF-1 (CXCL12) and its receptor CXCR4 on the migration and homing of MM cells. We demonstrated that CXCR4 is differentially expressed at high levels in the peripheral blood and is down-regulated in the bone marrow in response to high levels of SDF-1. SDF-1 induced motility, internalization, and cytoskeletal rearrangement in MM cells evidenced by confocal microscopy. The specific CXCR4 inhibitor AMD3100 and the anti-CXCR4 antibody MAB171 inhibited the migration of MM cells in vitro. CXCR4 knockdown experiments demonstrated that SDF-1–dependent migration was regulated by the PI3K and ERK/MAPK pathways but not by p38 MAPK. In addition, we demonstrated that AMD3100 inhibited the homing of MM cells to the bone marrow niches using in vivo flow cytometry, in vivo confocal microscopy, and whole body bioluminescence imaging. This study, therefore, demonstrates that SDF-1/CXCR4 is a critical regulator of MM homing and that it provides the framework for inhibitors of this pathway to be used in future clinical trials to abrogate MM trafficking.

01 Jan 1993·Developmental Pharmacology and Therapeutics

Studies on the Ontogeny of Goat Hepatic Cytochrome P-450- Associated O-Dealkylase Activities Using Monoclonal Antibodies: Comparison to Adult Lung Activity

Article

Author: Park, Sang-Shin ; Eltom, Sakina E. ; Schwark, Wayne S.

The P-450-associated O-dealkylase activity towards ethoxyresorufin (EROD) and pentoxyresorufin (PROD) was measured in liver microsomes from 1-day-, 1-week-, 4-week-, 6-week-old and adult goats in order to characterize the ontogeny of cytochrome P-450 in this species. The inhibition of these enzyme activities by monoclonal antibodies raised against 3-methyl-cholanthrene-induced (MAb 1-7-1) and phenobarbital-induced (MAb 2-66-3) rat hepatic cytochrome P-450 was used to measure the contribution of the MAb-defined, epitope-specific P-450 to the total activities during these ages of goat development. EROD activity was undetectable until the 1st week of life and increased more than 25-fold by 4 weeks of age. The inhibition of EROD by MAb 1-7-1 increased from 20% in 1-week-old to 70% in adult goats. PROD activity, however, was detectable in the 1-day-old and reached adult levels by 6 weeks of age. The maximal inhibition (40%) of PROD activity by MAb 2-66-3 was demonstrated in 1-day-old goats. The measurement of these enzyme activities and their inhibition by the monoclonal antibodies demonstrated major differences in the ontogeny of these P-450 isozymes in goats. On the other hand, adult goat lung lacked detectable PROD activity, while it expressed approximately one tenth of the EROD activity exhibited by the liver. Over 70% of this activity was inhibitable by MAb 1-7-1.

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Indication	Highest Phase	Country/Location	Organization	Date
Autoimmune Diseases	Discovery	US	Alexion Cambridge Corp.	-
Inflammation	Discovery	US	Alexion Cambridge Corp.	-

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