Superior immunomodulatory effects of intravenous immunoglobulins on human T-cells and dendritic cells: comparison to calcineurin inhibitors.
BACKGROUND
Prophylactic administration of anti-HBs intravenous immunoglobulins (IVIg) in hepatitis B infected-liver transplant patients protects against acute rejection. To explore the suitability of intravenous immunoglobulins (IVIg) as prophylaxis of acute rejection and graft-versus-host disease (GVHD) after allograft transplantation, the effects of IVIg and calcineurin inhibitors (CNI) on human blood-derived T-cells and DC were compared.


METHODS
T-cells were stimulated with phytohemagglutinin (PHA) or allogeneic spleen antigen-presenting cells (APC) and T-cell proliferation and cytokine production were determined in presence or absence of IVIg or CNI. Immature blood dendritic cells (DC) were stimulated in presence or absence of IVIg or CNI, and allogeneic T-cell stimulatory capacity, cell death, and phenotypic maturation were established.


RESULTS
IVIg and CNI equally inhibited T-cell proliferation and IFN-gamma production after PHA stimulation or allogeneic stimulation. CD8+ T-cells were preferentially affected by both IVIg and CNI after allogeneic stimulation. Like CNI, addition of IVIg at later time points after T-cell activation suppressed mitotic progression of responding T-cells. IVIg-treated DC were suppressed in their capacity to stimulate allogeneic T-cell proliferation by 73+/-12%, whereas DC-function was not affected by CNI. The decreased allogeneic T-cell stimulatory capacity of IVIg-treated DC correlated to induction of cell death in DC and decreased up-regulation of CD40 and CD80.


CONCLUSIONS
In vitro IVIg functionally inhibit the two principal immune cell-types involved in rejection and GVHD, i.e. T-cells and DC, whereas CNI only suppress T-cells. By targeting both T-cells and DC, IVIg may be a promising candidate for immunosuppressive treatment after allograft transplantation.
Tha-In
Thanyalak
T
Department of Gastroenterology and Hepatology, Erasmus MC, University Medical Center, Rotterdam, The Netherlands.
Metselaar
Herold J
HJ
Tilanus
Hugo W
HW
Boor
Patrick P C
PP
Mancham
Shanta
S
Kuipers
Ernst J
EJ
de Man
Robert A
RA
Kwekkeboom
Jaap
J
D019703:Calcineurin / Q000378:metabolism; D065095:Calcineurin Inhibitors; D002454:Cell Differentiation; D049109:Cell Proliferation; D002478:Cells, Cultured; D016207:Cytokines / Q000096:biosynthesis; D003713:Dendritic Cells / Q000166:cytology / Q000187:drug effects* / Q000276:immunology* / Q000378:metabolism; D006801:Humans; D016756:Immunoglobulins, Intravenous / Q000276:immunology* / Q000494:pharmacology* / Q000633:toxicity; D007155:Immunologic Factors / Q000276:immunology / Q000494:pharmacology / Q000633:toxicity; D010641:Phenotype; D013601:T-Lymphocytes / Q000166:cytology / Q000187:drug effects* / Q000276:immunology* / Q000378:metabolism
D065095:Calcineurin Inhibitors; D016207:Cytokines; D016756:Immunoglobulins, Intravenous; D007155:Immunologic Factors; D019703:Calcineurin