Induction of antigen-specific hyporesponsiveness by transplantation of hemopoietic cells containing an MHC class I transgene regulated by a lymphocyte-specific promoter.
We explored a novel approach to tolerance induction by the transplantation of bone marrow (BM) cells (BMCs) that themselves do not express a foreign histocompatibility Ag, but which give rise to mature lymphocytes that do so. Lines of transgenic (FVB) mice were generated that contained an MHC class I Dd cDNA regulated by a CD2 promoter. Because the CD2 promoter is lymphocyte-specific and activated relatively late in lymphocyte ontogeny, Dd is expressed on most mature lymphocytes in the periphery but only on developing B cells in the BM of transgenic mice. Transgenic BMCs are tolerogenic and reproducibly engraft in nontransgenic mice using a conditioning regimen that is nonpermissive for the engraftment of conventional (MHC promoter) Dd-transgenic BMCs. Engrafted BMCs generate transgene-expressing lymphocytes and confer a state of Ag-specific hyporesponsiveness on the host that is primarily attributable to a peripheral mechanism. The strategies by which tolerance can be optimized in this system are discussed.
Hansal
S A
SA
Laboratory of Immunology, Center for Biologics Evaluation and Research, Food and Drug Administration, Bethesda, MD 20892, USA.
Morris
D I
DI
Sechler
J M
JM
Love
P E
PE
Rosenberg
A S
AS
D000818:Animals; D001402:B-Lymphocytes / Q000378:metabolism; D016026:Bone Marrow Transplantation / Q000276:immunology; D018801:CD2 Antigens / Q000235:genetics; D000939:Epitopes / Q000276:immunology; D005786:Gene Expression Regulation / Q000276:immunology; D005805:Genes, MHC Class I; D006183:H-2 Antigens / Q000096:biosynthesis / Q000235:genetics; D018380:Hematopoietic Stem Cell Transplantation; D064532:Histocompatibility Antigen H-2D; D006801:Humans; D007108:Immune Tolerance; D051379:Mice; D008815:Mice, Inbred Strains; D008822:Mice, Transgenic; D011401:Promoter Regions, Genetic / Q000276:immunology*; D011828:Radiation Chimera / Q000276:immunology; D016038:Skin Transplantation / Q000276:immunology; D013601:T-Lymphocytes / Q000378:metabolism; D013934:Thymectomy; D019076:Transgenes / Q000276:immunology*
D018801:CD2 Antigens; D000939:Epitopes; D006183:H-2 Antigens; D064532:Histocompatibility Antigen H-2D