The effects of human macrophage inflammatory protein-1 alpha and its genetically modified variant, BB10010, on phagocyte function.
BB-10010 is a genetically modified form of human macrophage inflammatory protein-1 alpha (MIP-1 alpha) with a single amino acid substitution of Asp26 by alanine, which inhibits aggregation of the native molecule. BB-10010 has stem cell protective properties, and has entered clinical trials for this purpose. The aim of this study was to determine the effects of BB-10010 on human phagocyte function and compare them with the native molecule. MIP-1 alpha and BB-10010 had identical dose-response curves in assays of calcium mobilization; however, neutrophils were less sensitive than monocytes to either MIP-1 alpha form, suggesting differences in receptor expression. Neither MIP-1 alpha type directly stimulated phagocyte superoxide production, nor did it have any priming effect on agonist-induced superoxide production. Both MIP-1 alpha and BB-10010 enhanced monocyte migration; however, cells were more sensitive to the native molecule, with optimal effects seen at 1 ng/ml compared with 100 ng/ml BB-10010. Concomitant alteration of CD11b, CD18, and CD49d (VLA-alpha 4) cell adhesion molecule expression was not seen with either MIP-1 alpha type. With the exception of the difference in monocyte sensitivity in chemotaxis assays, BB-10010 reproduces the effects of the native molecule on phagocytes. BB-10010 does not have proinflammatory effects on neutrophil activation, and this bodes well for its clinical use.
Williams
S L
SL
Department of Haematology, University College London Medical School, UK.
Addison
I E
IE
Mollapour
E
E
Czaplewski
L G
LG
Linch
D C
DC
Roberts
P J
PJ
D002118:Calcium / Q000378:metabolism; D015815:Cell Adhesion Molecules / Q000378:metabolism; D002460:Cell Line; D054405:Chemokine CCL3; D054407:Chemokine CCL4; D014644:Genetic Variation; D016178:Granulocyte-Macrophage Colony-Stimulating Factor / Q000494:pharmacology; D006801:Humans; D066298:In Vitro Techniques; D007424:Intracellular Fluid / Q000378:metabolism; D019402:Macrophage Inflammatory Proteins / Q000235:genetics* / Q000494:pharmacology*; D009000:Monocytes / Q000187:drug effects / Q000502:physiology; D019255:NADPH Oxidases / Q000378:metabolism; D009504:Neutrophils / Q000187:drug effects / Q000502:physiology; D010586:Phagocytes / Q000187:drug effects* / Q000502:physiology; D011994:Recombinant Proteins; D016897:Respiratory Burst / Q000187:drug effects; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology
D015815:Cell Adhesion Molecules; D054405:Chemokine CCL3; D054407:Chemokine CCL4; D019402:Macrophage Inflammatory Proteins; D011994:Recombinant Proteins; D014409:Tumor Necrosis Factor-alpha; D016178:Granulocyte-Macrophage Colony-Stimulating Factor; D019255:NADPH Oxidases; D002118:Calcium