Abstract
Immune suppression with rabbit anti-thymocyte globulin (rATG) is a well-established therapeutic concept for preventing host rejection of transplanted organs and graft versus host disease. Increasing the efficiency of rATG production by reducing the number of animals would be highly beneficial to lower cost and to improve quality standards. We have developed transgenic (Tg) mice and rabbits that overexpress the neonatal Fc receptor (FcRn) and have shown an augmented humoral immune response in these animals. To test whether our FcRn Tg rabbits produced rATG more efficiently, we immunized them and their New Zealand White controls with live Jurkat cells. By day 21 after immunization, Tg animals produced significantly, 1.5 times higher amount of total IgG compared to their wt littermates. Also, the binding efficiency of Tg sera to Jurkat cells and their complement-mediated cytotoxicity was significantly higher. The purified Tg IgG preparation contained 2.6 the amount of Jurkat specific IgG as the wt preparation analyzed by complement-mediated lysis, suggesting greater antigen-specific B cell activation in the Tg rabbits. To test this hypothesis, immunization with ovalbumin and human α1-antitrypsin was performed, resulting in significantly greater numbers of antigen-specific B-cells in the FcRn Tg rabbits as compared with wt controls. The shift towards significantly larger populations of antigen-specific B cells relative to the non-specific B cell pool is further corroborated by our previous findings in FcRn Tg mice. Consequently, our FcRn Tg rabbits have the potential to offer substantial qualitative and quantitative improvements for the production of rATG and other polyclonal or monoclonal antibodies.
Highlights
Polyclonal Anti-Thymocyte Globulin (ATG) - the purified IgG fraction of serum from rabbits, horses, or less commonly goats immunized with human thymocytes or the Jurkat T-lymphoblastic cell line - contains antibodies with a wide range of specificities against antigens expressed on various normal and malignant hematopoietic cells including T, B, NK, and dendritic cells [1]
There is evidence that ATG-mediated immunosuppression is delivered in part via immunologically specific actions involving the generation of regulatory T cells [13,14]
ATG is widely used as a state of the art treatment for various clinical conditions including prevention or rescue treatment of acute rejection in organ transplantation [23], conditioning for hematopoietic stem cell transplantation, treatment of severe aplastic anemia, various autoimmune diseases, and more recently for the treatment of graft-versus-host disease [24]
Summary
Polyclonal ATG - the purified IgG fraction of serum from rabbits, horses, or less commonly goats immunized with human thymocytes or the Jurkat T-lymphoblastic cell line - contains antibodies with a wide range of specificities against antigens expressed on various normal and malignant hematopoietic cells including T-, B-, NK, and dendritic cells [1]. Due to its immunosuppressive potency, ATGs are extensively used in clinical applications, mainly in the field of human transplantation. These applications include therapy of aplastic anemia [2], conditioning of recipients of bone marrow transplantation [3,4], treatment of graft-versus-host disease after bone marrow transplantation [5,6], and prevention and treatment of acute rejection of organ allografts, including steroid resistant rejection [7]. There is evidence that ATG-mediated immunosuppression is delivered in part via immunologically specific actions involving the generation of regulatory T cells [13,14]
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