Local production of anti-CD4 antibody by transgenic allogeneic grafts affords partial protection

Background. Immunosuppressive drugs and antilymphocyte antibody are used cl inically to suppress cellular rejection responses. However, these systemic regimens often led to general immunodeficiency and thus increased susceptib ility to opportunistic infection and neoplasia, Immunosuppressive molecules delivered locally may be a way of inhibiting rejection responses, whereas systemic immunity is preserved, To achieve protective local immunosuppressi on, we produced a graft secreting its own immunomodulator, by deriving tran sgenic mice expressing a chimeric anti-CD4 antibody (GK2c) in the pancreas. Methods and Results. Transgenic mice in bm1 genetic background expressing a modified anti-mouse CD4 antibody (GK2c) under two promoters have been prod uced. Tissue expression of GK2c was detected by immunoperoxidase staining, Under the cytomegalovirus promoter, there was abundant GK2c expression in p ancreatic exocrine tissue. Under the rat preproinsulin II promoter, there w as abundant GK2e expression in pancreatic endocrine tissue only. High-expre ssion transgenic lines had 10-100 mu g/ml GK2c in blood plasma. By flow cyt ometry, these transgenic mice were devoid of CD4(+) cells in their peripher al lymphoid organs. To test transgenic mice as donors, fetal pancreata from transgenic mice were grafted into fully allogeneic CBA mice under the kidn ey capsule, transgenic grafts had prolonged survival compared with control non-transgenic grafts. Furthermore, GK2c transgenic grafts had reduced infi ltration with an absence of CD4(+) cells at the graft site without any effe ct on the cell composition in lymphatic tissues. Conclusion. Transgenic grafts that secrete anti-CD4 antibody can afford som e protection against graft rejection, while only affecting the CD4 populati on at the graft site.