Chemical compounds that target thiol-disulfide groups on mononuclear phagocytes inhibit immune mediated phagocytosis of red blood cells.
BACKGROUND
Patients having immune cytopenias produce antibodies that target hematopoietic cells resulting in their phagocytosis and intracellular destruction. Early reports suggested that phagocytosis could be inhibited by interfering with membrane thiol (SH) groups on phagocytes. Thus, whether chemical compounds that interact with SH or disulfide (SS) groups on mononuclear phagocytes can inhibit phagocytosis of antibody-coated cells was examined.


METHODS
A monocyte monolayer assay (MMA), which examines the in vitro monocyte-macrophage (Mphi) interaction with anti-Rh(D)-coated red cells (RBCs), was used to study the ability of different SH and SS chemicals to inhibit the Fc receptor-mediated phagocytosis of sensitized RBCs. The compounds examined included thimerosal, dithiothreitol (DTT), pentane-1-thiol, and two recently described SH and two SS chemicals that have been synthesized.


RESULTS
All compounds were found to be able to inhibit phagocytosis to varying degrees correlating to the structure of the molecule. In general, those compounds that interact with free SH groups to inhibit phagocytosis were found better than SH-containing compounds that interact with SSs. Thimerosal and p-nitrophenyl methyl disulfide were the most effective compounds inhibiting phagocytosis. Both chemicals showed greater than 50 percent inhibition at concentrations as low as 10(-9) mol per L. DTT was the least effective compound tested. Only thimerosal showed significant toxicity, as determined by decreased cell viability and increased apoptosis, but only at concentrations of 10(-8) mol per L. The effect of chemical treatment was on attachment rather than on phagocytosis itself. Fcgamma receptor-independent endocytosis was not affected by the chemical treatment.


CONCLUSIONS
These studies indicate that pharmacologic strategies that target SH groups on mononuclear phagocytes may have future efficacy for the treatment of immune cytopenias.
Rampersad
Gregory C
GC
Research & Development, Canadian Blood Services, Toronto, Ontario, Canada.
Suck
Garnet
G
Sakac
Darinka
D
Fahim
Soad
S
Foo
Alison
A
Denomme
Gregory A
GA
Langler
Richard F
RF
Branch
Donald R
DR
D000906:Antibodies / Q000276:immunology; D004220:Disulfides / Q000737:chemistry / Q000276:immunology*; D004229:Dithiothreitol / Q000494:pharmacology; D004705:Endocytosis / Q000276:immunology; D004912:Erythrocytes / Q000276:immunology*; D006801:Humans; D008264:Macrophages / Q000276:immunology; D009000:Monocytes / Q000276:immunology; D010586:Phagocytes / Q000276:immunology*; D010587:Phagocytosis / Q000187:drug effects / Q000276:immunology*; D011310:Preservatives, Pharmaceutical / Q000737:chemistry / Q000494:pharmacology; D017452:Receptors, IgG / Q000276:immunology; D012204:Rh-Hr Blood-Group System / Q000276:immunology; D013438:Sulfhydryl Compounds / Q000737:chemistry / Q000276:immunology*; D013849:Thimerosal / Q000737:chemistry / Q000494:pharmacology
D000906:Antibodies; D004220:Disulfides; D011310:Preservatives, Pharmaceutical; D017452:Receptors, IgG; D012204:Rh-Hr Blood-Group System; C026410:Rho(D) antigen; D013438:Sulfhydryl Compounds; D013849:Thimerosal; D004229:Dithiothreitol