I have now read the following papers:
J Immunol (1999) 162:3402
J Immunol (1999) 163:3785
Transplantation (1999) 68(4):480
Transplantation (1999) 68(11):1684
My feeling on BTRN's technology are mixed.
1. MIXED LYMPHOHEMATOPOETIC CHIMERISM FOR ALLOTRANSPLANTATION TOLERANCE INDUCTION: Using mixed chimerism as a method to induce tolerance to allotransplants of solid organs is nothing new. What is new is the demonstration of such an event in a human subject. Several questions remain to be answered: (a) Can a meaningful graft versus tumour immunity be sustained in the face of donor specific tolerance. The fact that multiple DLIs did not result in GVHD may suggest that GVT may also be lost. This will be of major importance if this strategy is applied to solid tumours such as breast cancer. (b) Can a company patent a procedure which utilizes conventional therapeutics in a defined manner which is already in the public domain and if so, is it reasonable to believe that such a patent is policeable. And (c) from a scientific point of view I would love to know more about the role of thymic irradiation in inducing allo-tolerance in adults. Overall, I think that the results are very exciting but may be difficult to protect from an intellectual property perspective.
2. XENOGRAFT TOLERANCE VIA THYMOKIDNEY: Here I am much less excited at the potential for success in the next decade (at the least). Xeno-tolerance represents probably the most difficult barrier to cross for immunologists. Everything is stacked against you. If you make it past the preformed antibodies, the NK will get you. If you make it past the NK, an acute adaptive immune response will get you. If you manage to avoid teh acute attack, epitope spreading will kill you. And if you are so genius as to induce tolerance, the ethics committees will stop you anyway because of the possibility of passing pathogens between species, or even worse, facilitating the mutation of a pathogen which cannot infect humans into one which can (a current model for the evolution of HIV via mass polio vaccination using primate serum products which were contaminated with SIV). What a nightmare. In any case, BTRN is still far from breaking ground on obstacle number 2 and to get that far they will have to remove the preformed antibodies and pay rolyalties to another company. So far, BTRN has demonstrated that porcine thymic grafts can support the education of a "normal" allogeneic porcine, murine and human T cell repetoire and even rescue an immunocompromised one. This is a very interesting observation but it is so far not clinically relavent because all of the studies were carried out in either immunodeficient animals (SCID mice) or previously donor tolerized swine. The thymokidney is a brilliant idea for transplanting a "healthy" thymus but the latest JI paper (1999, 63:3785) would argue that T cell mediated tolerance is transient at best while humoral tolerance was not obtained. Further, rejection of donor skin grafts was the big red flag anyway that roadblock number 2 was still very solidly intact. Other preconditioning protocols which include T/NK depletion etc. may hold more promise but when it comes to xenotransplantation I have learned never to hold my breath. That said, I still find Megan Sykes' work very exciting, I just think there are safer bets out there.
PM |
