application abstract): Before laryngotracheal allotransplantation can be clinically applied, the benefits of transplantation must be weighed against the risk of immunosuppression. The induction of donor specific immune tolerance to tracheal allografts would avoid the toxic side effects associated with the chronic use of non-specific immunosuppression. Intrathymic inoculation of donor antigen has been shown to induce centrally mediated negative selection. Similarly, under special conditions, foreign antigen presented peripherally can also result in the development of tolerance. The form and route of antigen administration play a crucial role in determining whether an antigen will be perceived as immunogenic or tolerogenic. It was initially observed that oral administration of antigen resulted in a tolerogenic state. Anticipating the focal role of the liver in this process, this concept has been extended to direct portal venous administration of donor antigen, which results in a similar antigen-specific unresponsive state. The inability of ultraviolet B (WEB) treated splenocytes to stimulate allogeneic cells in vitro, subsequently has been applied in vivo to confer, through intraportal administration of donor antigen, a potent donor specific immune tolerance. The applicant has demonstrated donor specific tolerance to peripheral nerve allografts in the rat model, and preliminarily, tracheal allografts, after a single intraportal inoculation of UVB irradiated donor spleen cells. Before laryngeal allotransplantation can be successfully investigated, it is essential to establish immune tolerance to the components of the larynx, specifically, nerve and the tracheal complex. The applicant has previously established tolerance to peripheral nerve allografts in the rat model, and currently, is investigating the mechanism of tolerance induction. Therefore, in this application, it is planned to examine and define the mechanism responsible for allograft tolerance resultant from a peripheral inoculation of donor antigen and examine alternative methods for inducing immune tolerance and preventing rejection of tracheal allografts and eventually, laryngeal allografts.
Specific Aim I will focus on determining the mechanism of tolerance as a result of portal venous administration of donor antigen.
Specific Aim II will focus on alternative methods of inducing donor specific tolerance to tracheal allografts.
Specific Aim III will focus on the behavior of the tracheal allograft and its affect upon the established state of tolerance.
| Cleven, Heidi A; Genden, Eric M; Moran, Thomas M (2005) Reepithelialized orthotopic tracheal allografts expand memory cytotoxic T lymphocytes but show no evidence of chronic rejection. Transplantation 79:861-8 |
| Genden, Eric M; Govindaraj, Satish; Chaboki, Houtan et al. (2005) Reepithelialization of orthotopic tracheal allografts prevents rejection after withdrawal of immunosuppression. Ann Otol Rhinol Laryngol 114:279-88 |
| Govindaraj, Satish; Gordon, Ronald; Genden, Eric M (2004) Effect of fibrin matrix and vascular endothelial growth factor on reepithelialization of orthotopic murine tracheal transplants. Ann Otol Rhinol Laryngol 113:797-804 |
| Genden, Eric M; Gannon, Patrick J; Smith, Shane et al. (2003) Microvascular transplantation of tracheal allografts model in the canine. Ann Otol Rhinol Laryngol 112:307-13 |
| Genden, Eric M; Iskander, Andrew; Bromberg, Jonathan S et al. (2003) The kinetics and pattern of tracheal allograft re-epithelialization. Am J Respir Cell Mol Biol 28:673-81 |
| Genden, Eric M; Iskander, Andrew J; Bromberg, Jonathan S et al. (2003) Orthotopic tracheal allografts undergo reepithelialization with recipient-derived epithelium. Arch Otolaryngol Head Neck Surg 129:118-23 |
| Genden, Eric M; Boros, Peter; Liu, Jianhua et al. (2002) Orthotopic tracheal transplantation in the murine model. Transplantation 73:1420-5 |
| Genden, Eric M; Gannon, Patrick J; Smith, Shane et al. (2002) Microvascular transfer of long tracheal autograft segments in the canine model. Laryngoscope 112:439-44 |
| Genden, E M; Mackinnon, S E; Yu, S et al. (2001) Portal venous ultraviolet B-irradiated donor alloantigen prevents rejection in circumferential rat tracheal allografts. Otolaryngol Head Neck Surg 124:481-8 |
