Immunomodulatory activity of a methionine aminopeptidase-2 inhibitor on B cell differentiation.
Methionine aminopeptidase-2 (MetAP-2) inhibitors have potent anti-angiogenesis activity and are being developed for the treatment of solid tumours. The recently observed specific expression of MetAP-2 in germinal centre B cells suggests that it has a role in regulating B cell function. We have demonstrated a potent MetAP-2-dependent inhibitory effect on the antibody secretion from B cell receptor and CD40 co-stimulated primary human B cells in the presence of interleukin-21. The effect of MetAP-2 inhibition on antibody secretion was due to a block in differentiation of B cells into plasma cells. Immunohistochemical analysis of germinal centres from human, mouse and marmoset spleen showed a similar expression pattern of MetAP-2 in the marmoset and man, whereas mouse spleen showed no detectable expression. In a marmoset, T dependent immunization model, the MetAP-2 inhibitor suppressed an antigen-specific antibody response. Furthermore, histological analysis showed loss of B cells in the spleen and disrupted germinal centre formation. These results provide experimental evidence to support a novel role for MetAP-2 in immunomodulation. These effects of MetAP-2 are mediated by disruption of the germinal centre reaction and a block in the differentiation of B cells into plasma cells.
Priest
R C
RC
II CEDD, GlaxoSmithKline, Gunnel's Wood Road, Stevenage, Hertfordshire, UK. richard.c.priest@gsk.com
Spaull
J
J
Buckton
J
J
Grimley
R L
RL
Sims
M
M
Binks
M
M
Malhotra
R
R
D000626:Aminopeptidases / Q000032:analysis / Q000037:antagonists & inhibitors*; D000818:Animals; D000906:Antibodies / Q000276:immunology; D001402:B-Lymphocytes / Q000166:cytology / Q000187:drug effects* / Q000276:immunology; D002144:Callithrix; D002454:Cell Differentiation / Q000187:drug effects; D003864:Depression, Chemical; D004797:Enzyme-Linked Immunosorbent Assay / Q000379:methods; D004852:Epoxy Compounds / Q000494:pharmacology*; D018858:Germinal Center / Q000737:chemistry / Q000187:drug effects; D006801:Humans; D007074:Immunoglobulin G / Q000032:analysis; D007150:Immunohistochemistry; D018655:Lymphocyte Count; D008666:Metalloendopeptidases / Q000032:analysis / Q000037:antagonists & inhibitors*; D051379:Mice; D023421:Models, Animal; D013045:Species Specificity; D013154:Spleen / Q000276:immunology; D014633:Valine / Q000031:analogs & derivatives* / Q000494:pharmacology
D000906:Antibodies; D004852:Epoxy Compounds; D007074:Immunoglobulin G; C488724:PPI 2458; D000626:Aminopeptidases; C106541:methionine aminopeptidase 2; D008666:Metalloendopeptidases; D014633:Valine