Expression of an allogeneic MHC DRB transgene, through retroviral transduction of bone marrow, induces specific reduction of alloreactivity.
BACKGROUND
Transfer of MHC class II genes, through allogeneic bone marrow (BM) transplantation, induced long-lasting acceptance of renal allografts in miniature swine. To adapt this approach to the clinic, we have now examined whether somatic transfer of allogeneic class II DR genes, into otherwise autologous bone marrow cells (BMC), can provide the matching required for inducing immune tolerance.


METHODS
Autologous BMC were transduced ex vivo with recombinant retroviruses for allogeneic DRB followed by BM transplantation. The recipients were then challenged with kidney allografts solely matched to the DRB transgene.


RESULTS
Five miniature swine received autologous BMC conditioned with growth factors and transduced with recombinant retrovirus vectors containing allogeneic (n=4) or syngeneic (n=1) class II DRB genes and a drug-resistance marker. Expression of retrovirus-derived products in BM-derived cells was demonstrated by the detection of drug-resistant colony-forming progenitors and the presence of DRB retrovirus transcripts in peripheral cells. Analysis of selective mixed lymphocyte reaction responses to DR or DQ antigens indicated decreased reactivity toward the transduced DR gene product. Among all of the animals receiving fully mismatched kidney allografts, but with DRB matched to the transduced DRB, the one with the highest gene transduction rate showed stable allograft function and essentially normal renal histology for 2.5 years. A control animal, which received a syngeneic DRB gene, rejected its kidney allograft in 120 days after an earlier rejection crisis.


CONCLUSIONS
These studies demonstrate that allogeneic MHC gene transfer into BM provides a new strategy for inducing tolerance across MHC barriers.
Emery
D W
DW
Transplantation Biology Research Center, Massachusetts General Hospital/Harvard Medical School, Boston 02129, USA.
Sablinski
T
T
Shimada
H
H
Germana
S
S
Gianello
P
P
Foley
A
A
Shulman
S
S
Arn
S
S
Fishman
J
J
Lorf
T
T
Nickeleit
V
V
Colvin
R B
RB
Sachs
D H
DH
LeGuern
C
C
D000818:Animals; D001854:Bone Marrow Cells / Q000821:virology; D016026:Bone Marrow Transplantation / Q000276:immunology; D016207:Cytokines / Q000494:pharmacology; D015870:Gene Expression; D006684:HLA-DR Antigens / Q000096:biosynthesis / Q000235:genetics*; D000949:Histocompatibility Antigens Class II / Q000096:biosynthesis / Q000235:genetics*; D006650:Histocompatibility Testing; D006822:Hybrid Cells / Q000378:metabolism; D007518:Isoantibodies / Q000276:immunology; D016030:Kidney Transplantation / Q000276:immunology; D007959:Lymphocyte Culture Test, Mixed / Q000379:methods; D012190:Retroviridae / Q000502:physiology; D013552:Swine; D013556:Swine, Miniature; D013601:T-Lymphocytes / Q000276:immunology; D014161:Transduction, Genetic / Q000187:drug effects; D019076:Transgenes
D016207:Cytokines; D006684:HLA-DR Antigens; D000949:Histocompatibility Antigens Class II; D007518:Isoantibodies