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Delayed rejection of soluble tumor necrosis factor receptor-secreting tumor allografts
M S Sabatine1, T Laufer, L H Glimcher
1Transplantation Unit of the General Surgical Service, Massachusetts General Hospital and Harvard Medical School, Boston 02114, USA.
Background:
Exogenous soluble tumor necrosis factor receptor (TNFR) has been shown to be an effective immunosuppressant. It has yet to be tested whether tissues secreting soluble TNFR, when transplanted into a foreign host, could locally generate immunosuppression and therefore manifest prolonged survival.
Methods:
A murine tumor line was transfected with the gene encoding a chimeric protein consisting of the extracellular domain of the human 75-kDa TNFR fused to the Fc region of the human IgG1 heavy chain. This tumor line was then injected into allogeneic recipients.
Results:
Transfected tumor cells were shown to secrete soluble TNFR. When transplanted into minor histocompatibility antigen-disparate allogeneic recipients, these tumor cells grew as a solid tumor and resisted rejection, whereas untransfected tumors and interleukin-4 receptor transfectant controls were rejected within 4 weeks. The resistance to rejection could be reversed by coadministration of an anti-TNFR monoclonal antibody.
Conclusions:
Prolongation of graft survival can be achieved by genetically altering transplanted tissue to secrete soluble cytokine receptors.