Prolonged survival of mouse skin allografts after transplantation of fetal liver cells transduced with hIL-10 gene.
BACKGROUND
Interleukin-10 (IL-10) is a cytokine with a moleculary weight of 18 kDa, that was first identified as being produced by Th2 cells. It appears to have anti-inflammatory action by diminishing the production of pro-inflammatory cytokines produced by Th1 cells. IL-10 also regulates the differentiation and proliferation of several immune cells such as T cells, B cells, natural killer cells, antigen-presenting cells, mast cells and granulocytes. Recent data suggest, however, that IL-10 also has immunostimulatory properties with important consequences on the prognosis of disease. In this study, we demonstrate the importance of injection of hematopoietic fetal liver cells transduced with the human IL-10 (hIL-10) gene into an allogenic recipient subsequently transplanted with allogenic skin grafts. The immaturity of stem cells and precursor cells from fetal liver and their transient survival in the host, due to the production of hIL-10, may afford 'prope' tolerance. It also explains the lack of graft-vs.-host reaction (GvHR) and the delay in rejection of the specific donor skin grafts after virtual disappearance of donor hematopoietic cells.


OBJECTIVE
Transduction of CBA hematopoietic fetal cells with the human IL-10 gene was used with the aim of inducing tolerance to donor antigen in recipient BALB/c mice. The observed effects were prolonged IL-10 production, donor cell chimerism in the host and delayed rejection of skin grafts from the specific donor strain.


METHODS
To prevent or delay rejection of highly incompatible skin allografts, we used IL-10 gene transfer to establish chimerism with donor hematopoietic cells. Fetal liver cells from CBA mice were transduced with the human IL-10 gene and injected into BALB/c mice.


RESULTS
Human IL-10, which is active in mice but does not cross-react with murine IL-10 in ELISA, was produced in vivo for 3 weeks. Donor cells were identified in the recipients during the same time period, on the basis of presence of the H-2 k gene and human IL-10 intracellular protein. Skin allografts from CBA or C57BL/6 mice survived for a mean of 9.5 days in recipient mice injected with non-transduced cells. In contrast, survival of CBA allograft was extended to 18.9+/-1.8 days in recipients injected with hIL-10-transduced fetal liver cells from CBA mice. Human IL-10 alone, without donor hematopoietic cell engraftment, did not prolong graft survival (9.6+/-1.2 days).


CONCLUSIONS
IL-10 transduction of donor hematopoietic stem cells resulted in production of IL-10, cell engraftment and chimerism. Although full tolerance was not obtained at this level of donor cell development in the host, a specific and highly significant (P<0.001) prolongation of the survival of donor skin allografts was observed.
Sembeil
Rachel
R
Department of Transplantation and Clinical Immunology, Claude Bernard University and Hôpitaux de Lyon, France.
Sanhadji
Kamel
K
Vivier
Geneviève
G
Chargui
Jamel
J
Touraine
Jean-Louis
JL
D000818:Animals; D000950:Antigens, Ly / Q000032:analysis / Q000276:immunology; D001854:Bone Marrow Cells / Q000276:immunology; D046528:Chimerism; D005333:Fetus / Q000166:cytology; D006082:Graft Enhancement, Immunologic / Q000379:methods*; D006085:Graft Survival; D006183:H-2 Antigens / Q000032:analysis / Q000276:immunology; D018380:Hematopoietic Stem Cell Transplantation / Q000379:methods*; D022781:Hepatocytes / Q000276:immunology / Q000378:metabolism / Q000637:transplantation; D016753:Interleukin-10 / Q000032:analysis / Q000235:genetics*; D008099:Liver / Q000166:cytology* / Q000196:embryology; D008565:Membrane Proteins / Q000032:analysis / Q000276:immunology; D051379:Mice; D016038:Skin Transplantation / Q000276:immunology / Q000379:methods*; D014161:Transduction, Genetic; D018183:Transplantation Chimera / Q000276:immunology; D023001:Transplantation Tolerance / Q000235:genetics / Q000276:immunology
D000950:Antigens, Ly; D006183:H-2 Antigens; C074650:Ly6a protein, mouse; D008565:Membrane Proteins; D016753:Interleukin-10