sHLA-I contaminating molecules as novel mechanism of ex vivo/in vitro transcriptional and posttranscriptional modulation of transforming growth factor-beta in CD8+ T lymphocytes and neutrophils after intravenous immunoglobulin treatment.
BACKGROUND
Numerous mechanisms have been proposed to explain the beneficial action of intravenous immune globulin (IVIG) in autoimmune and systemic inflammatory disorders. Among others' data, an in vitro increase of intracellular TGF-beta expression when culturing CD4+ T lymphocytes in the presence of IVIG has been reported. As IVIG infusion involves administration of soluble contaminants likewise all hemoderivative preparations, we hypothesized that, besides several other immunomodulatory proposed mechanisms, the clinical effects of IVIG therapy might be, at least partly, due to contaminating soluble HLA Class I (sHLA-I) molecules capable to exert pleiotropic immunomodulatory effects among which TGF-beta(1) modulation.


METHODS
Ex vivo and in vitro transcriptional and posttranscriptional modulation of TGF-beta(1) in CD8+ T lymphocytes and neutrophils after IVIG infusion was analyzed.


RESULTS
Ex vivo analysis of cells drawn from 10 enrolled IVIG recipients pointed out a significant increase of TGF-beta(1) mRNA and intracellular TGF-beta(1) molecules in both leukotypes. In vitro comparable results were obtained incubating CD8+ T lymphocytes and neutrophils from healthy donors with IVIG. The immunodepletion of sHLA-I and/or soluble Fas ligand (sFasL) abolished TGF-beta(1) modulation in both leukotypes. Coculture with human immunoglobulin (Ig)M monoclonal antibody or chimeric IgG (MabThera, Roche), whose manufacturing excludes "contamination," did not exert any mRNA modulation. Finally, IgM or MabThera plus purified sHLA-I molecules enhanced TGF-beta(1) mRNA in both white blood cells to levels comparable to those obtained with IVIG incubation.


CONCLUSIONS
On the whole, these data lead us to speculate that the ability of IVIG administration to modulate TGF-beta(1) might be related to the immunomodulatory activities of sHLA-I and sFasL molecules on activated CD8+ T lymphocytes and neutrophils.
Ghio
Massimo
M
Division of Clinical Immunology and Internal Medicine, University of Genoa Medical School, Genoa, Italy. mghio@unige.it
Contini
Paola
P
Negrini
Simone
S
Proietti
Michele
M
Gonella
Roberta
R
Ubezio
Gianluca
G
Ottonello
Luciano
L
Indiveri
Francesco
F
D000911:Antibodies, Monoclonal / Q000494:pharmacology; D018414:CD8-Positive T-Lymphocytes / Q000378:metabolism*; D002478:Cells, Cultured; D053222:Fas Ligand Protein / Q000008:administration & dosage / Q000494:pharmacology; D005260:Female; D015395:Histocompatibility Antigens Class I / Q000008:administration & dosage / Q000494:pharmacology; D006801:Humans; D016756:Immunoglobulins, Intravenous / Q000008:administration & dosage / Q000494:pharmacology; D007155:Immunologic Factors / Q000008:administration & dosage / Q000494:pharmacology; D008213:Lymphocyte Activation / Q000187:drug effects; D008297:Male; D009504:Neutrophils / Q000378:metabolism*; D012333:RNA, Messenger / Q000096:biosynthesis; D014158:Transcription, Genetic / Q000187:drug effects*; D053773:Transforming Growth Factor beta1 / Q000096:biosynthesis*
D000911:Antibodies, Monoclonal; D053222:Fas Ligand Protein; D015395:Histocompatibility Antigens Class I; D016756:Immunoglobulins, Intravenous; D007155:Immunologic Factors; D012333:RNA, Messenger; D053773:Transforming Growth Factor beta1