Inhibition of xenoreactive antibodies

Details Inhibition of xenoreactive antibodies Inhibition of xenoreactive antibodies

1999-04-15

2003-06-03

Celsa, Bennett (Department: 1639)

Drug, bio-affecting and body treating compositions

Nonspecific immunoeffector, per se ; or nonspecific...

C424S184100, C424S193100, C424S194100, C424S279100, C424S280100, C514S023000

Reexamination Certificate

active

06572867

ABSTRACT:

TECHNICAL FIELD OF THE INVENTION
This invention is in the general field of pharmaceuticals for treatment of conditions caused by xenoreactive antibodies.
BACKGROUND
Organ Transplantation
Organ transplantation is now widely viewed as the preferred treatment for end stage organ failure, based on both a quality of life and cost basis. One year graft survival for kidney and heart transplantation at the major transplant centers is now greater than 90% with acute rejection rates less than 30%. There are approximately 2500 heart transplants and 12,500 kidney transplants performed every year in the USA. The major limitation to more widespread utilization of this procedure is a shortage of available organs. This can be seen by looking at the transplant waiting list, which shows that more than twice the number of people are waiting for an organ than could ever receive one. Additionally, 10 people per day die while waiting for a transplant. The demand for organs, however, is much greater than the number of people on the transplant waiting list. There are 125,000 patients in end stage renal failure who theoretically could benefit from a transplant. It is also been estimated that 25,000 to 40,000 people could benefit from a heart transplant if a donor organ were available.
The availability of human organs is not likely to increase in any significant way over the next few years and even if all of the potential human donor organs could be utilized this would only increase the number of organs transplanted by about 2 fold, far less than the actual demand. Possible mechanical solutions to this problem such as left ventricular assist devices for cardiac failure while adequate at least for temporary support appear unlikely to provide for a long-term solution and as yet no implantable device exists for a kidney. Indeed, renal transplantation is viewed as superior and preferred in terms of the quality of life compared to dialysis. Given these alternatives the medical and scientific communities have turned to animals to provide for a solution to the organ shortage problem.
Animals as Donors
The preferred animal species for transplantation to humans is the pig. Although the closely related non-human primate species are immunologically more similar to humans, and therefore the rejection process which is seen upon transplantation could likely be more easily controlled by current immunosuppressive drugs, a number of reasons make this possibility remote. First, a non-human primate of appropriate size for a heart transplant into an adult human would be a chimpanzee or equivalent large animal. These animals are on the endangered species list and thus would raise significant ethical questions even if it were possible to breed large numbers in captivity. The most abundant non-human primate, which is the baboon, is small and could not provide hearts for transplantation into adult humans although conceivably kidneys or livers would be possible. However, the baboon contains a number of potentially pathogenic organisms which could present a problem if transmitted to a human, and the generation of large numbers of specific pathogen free animals would be extremely costly and time consuming. The pig, a domesticated farm animal, on the other hand is of an appropriate size, can be raised to obtain specific pathogen free animals and is available in large numbers. Clearly, if the immunological problems could be overcome the pig would be the ideal donor to solve the organ shortage problem.
The Immunological Problem
The initial barrier to transplantation of a pig organ to primates is a process of hyperacute rejection which results in the loss of the graft within a few minutes to hours of transplantation and is characterized histologically by thrombosis, hemorrhage, edema and a lack of a cellular infiltrate (Platt, J. L., et al.,
Immunology Today
11:450-456, 1990). This process is initiated by the binding of antibody, which is already present in the recipient, to the graft endothelium, and the resulting activation of the complement cascade. A similar process can be seen in allografts when antibody is present in the recipient prior to transplantation. In thinking about the pig as a donor, it is useful to review the effect of pre-existing antibodies on allograft survival and what strategies are important in obtaining prolonged graft survival.
The presence of antibody in the serum of an allograft recipient, which recognizes antigen present on the donor endothelium, can be an indicator of a poor prognosis for long-term graft survival. Indeed, in a percentage of these allografts a rapid process of rejection, as described above for pig to primate xenografts, in which the graft is lost within a few minutes to hours after reperfusion, can occur. An example of this situation is seen when the donor and recipient are incompatible with regard to the blood group ABO system. The blood group antigen, which is a carbohydrate, is present on the donor endothelium. When a graft from a blood group A donor is transplanted into a blood group O recipient, in which antibody against the blood group A antigen is present, antibody is deposited in the graft. In the case of these grafts in which hyperacute rejection occurs the binding of antibody to the graft endothelium causes complement to be fully activated which results in damage to the endothelium and subsequent loss of the endothelial barrier function resulting in thrombosis, hemorrhage, edema and irreversible graft failure. If hyperacute rejection does not occur many, though clearly not all, of the grafts are lost due to vascular rejection in the subsequent weeks to months. These transplants were initially performed in the pre-cyclosporin era and led to the suggestion that matching for ABO compatibility should be performed prior to transplantation.
As the success of allografts improved, dramatic shortages in the availability of organs led a number of groups to reassess the possibility of transplanting across the ABO barrier particularly in the case of living related kidney donors. These investigators found that in order to routinely prevent hyperacute rejection and achieve optimal long term graft survival, comparable to that obtained with ABO matched grafts, the antibody present at the time of transplant has to be temporarily removed usually by physical means such as immunoapheresis. A standard or in some cases an enhanced immunosuppression protocol is then applied. Under these circumstances the long-term outcome for these grafts is as good as would be obtained with ABO compatible grafts. In a percentage of these ABO incompatible grafts antibody apparently returns to the circulation but the graft is not rejected and this phenomenon has been termed “accommodation”. However, it is still far from clear that this antibody as detected in standard haemagglutination reactions is actually capable of binding to the graft. In many circumstances the antibody does not return in a detectable form to the circulation, although it is certainly conceivable that antibody is bound to the graft.
In a pig to primate xenograft, the xenoreactive antibody which is found in the recipient prior to transplant predominantly if not exclusively recognizes the unique carbohydrate structure, &agr;Gal(1,3)Gal. This structure is found as the terminal sugar on glycolipids and glycoproteins present on the donor pig endothelium. The pig and many other mammals but not humans or Old World monkeys synthesize this epitope. This scenario is in many ways reminiscent of the ABO blood group mismatched allografts described above. In a similar fashion to the mammalian blood group antigens such as the human blood group A, the lack of the antigen in an animal results in the synthesis of antibodies which recognize it. This antibody is probably induced and stimulated on an ongoing basis by gut bacteria, which possess a related structure. Indeed, Galili et. el (1988) showed that anti-Gal antibodies bound to a variety of enterobacteria such as
E.coli
, klebsiella and salmonella. The Gal reactive structure varied between the bacteria and was

Affiliated with

Also associated with

Rating

Inhibition of xenoreactive antibodies does not yet have a rating. At this time, there are no reviews or comments for this patent.

If you have personal experience with Inhibition of xenoreactive antibodies, we encourage you to share that experience with our LandOfFree.com community. Your opinion is very important and Inhibition of xenoreactive antibodies will most certainly appreciate the feedback.

Rate now

Comments { 0 }

Profile ID: LFUS-PAI-O-3098037