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.
Laboratory of Immunology, Center for Biologics Evaluation and Research, Food and Drug Administration, Bethesda, MD 20892, USA.
S A
SA
Hansal
D I
DI
Morris
J M
JM
Sechler
P E
PE
Love
A S
AS
Rosenberg
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