Intravenous immunoglobulins promote skin allograft acceptance by triggering functional activation of CD4+Foxp3+ T cells.
BACKGROUND
Intravenous immunoglobulins (IVIg) therapy is effective as a treatment for T-cell-mediated immune diseases, but whether and how IVIg suppress allogeneic T-cell responses is largely unknown.


METHODS
In vitro, human CD4(+), CD4(+)CD25(-), or CD4(+)CD25(+) T cells were stimulated with allogeneic antigen-presenting cells (APCs), and mouse CBA/Ca (H2(k)) CD4(+) or CD4(+)CD25(-) T cells were stimulated with C57BL/10 (H2(b)) splenocytes, in the presence or absence of IVIg. Proliferation, binding of IVIg, expression of activation markers, and ZAP70-phosphorylation were determined. In vivo, 1x10(5) CD4(+) or CD4(+)CD25(-) T cells of CBA/Ca mice were adoptively transferred into CBA/RAG1(-/-) mice, which were 1 day later transplanted with skin grafts of C57BL/10 mice. IVIg was administered intravenously and skin graft survival was determined.


RESULTS
IVIg bound to the surface of human and mouse CD4(+)Foxp3(+) regulatory T cells (Tregs). IVIg binding resulted in functional activation of Tregs, as detected by increased expression of surface activation markers, enhanced ZAP70-phosphorylation, and increased capacity to suppress allogeneic T-cell proliferation. IVIg inhibited allogeneic T-cell proliferation in the presence of Tregs, but this effect was abrogated on selective depletion of CD25(+) cells from responder T cells. IVIg prevented T-cell-mediated rejection of fully mismatched skin grafts in CBA/RAG1(-/-) mice reconstituted with CD4(+) T cells, but this effect was lost on selective depletion of CD4(+)CD25(+) cells from transferred T cells, indicating that IVIg induced dominant allograft protection mediated by Tregs.


CONCLUSIONS
Our data show that IVIg suppress allogeneic T-cell responses by direct activation of Tregs. IVIg treatment, which has been proven safe, may have therapeutic potential in tolerance-inducing strategies in transplant medicine.
Tha-In
Thanyalak
T
Department of Gastroenterology and Hepatology, Erasmus MC-University Medical Center, Rotterdam, The Netherlands.
Metselaar
Herold J
HJ
Bushell
Andrew R
AR
Kwekkeboom
Jaap
J
Wood
Kathryn J
KJ
D000818:Animals; D015496:CD4-Positive T-Lymphocytes / Q000166:cytology*; D005434:Flow Cytometry / Q000379:methods; D051858:Forkhead Transcription Factors / Q000096:biosynthesis*; D006085:Graft Survival; D006801:Humans; D016756:Immunoglobulins, Intravenous / Q000378:metabolism*; D053645:Interleukin-2 Receptor alpha Subunit / Q000096:biosynthesis; D051379:Mice; D008810:Mice, Inbred C57BL; D008808:Mice, Inbred CBA; D018345:Mice, Knockout; D008954:Models, Biological; D016038:Skin Transplantation / Q000276:immunology* / Q000379:methods*; D013601:T-Lymphocytes / Q000166:cytology*
C418974:FOXP3 protein, human; D051858:Forkhead Transcription Factors; D016756:Immunoglobulins, Intravenous; D053645:Interleukin-2 Receptor alpha Subunit