Organic compounds -- part of the class 532-570 series – Organic compounds – Carbohydrates or derivatives
Reexamination Certificate
1997-05-09
2001-07-24
Achutamurthy, Ponnathapu (Department: 1652)
Organic compounds -- part of the class 532-570 series
Organic compounds
Carbohydrates or derivatives
C536S023200, C536S023500, C435S320100
Reexamination Certificate
active
06265557
ABSTRACT:
BACKGROUND OF THE INVENTION
The transplantation of organs to patients having organ diseases or defects was at first limited by technical obstacles to transplantation surgery, and later by the lack of effective immunosuppressive agents. As many of these obstacles were overcome, the major limiting factor quickly became the scarcity of suitable donor organs. While public information campaigns have made headway in convincing people of the importance of designating themselves as potential organ donors, there is still a severe shortage of organs for transplantation. Many patients can only wait as their condition worsens, uncertain of whether a suitable organ will become available before they are too ill to benefit from a transplant.
An obvious limit on the number of vital organs for transplantation is the fact that such organs only become available under unusual circumstances: the death of an otherwise relatively healthy person in a manner that does not damage the vital organs. Therefore, vital organs for human allotransplantation (transplantation between individuals of the same species) will likely always be in short supply. Accordingly, xenotransplantation (transplantation between individuals of different species) provides a desirable additional source of organs for transplantation to humans.
In the development of an optimal xenotransplantation system, several factors must be considered. First, a close phylogenetic relationship between the donor and the recipient is preferable to a more distant relationship. For example, for xenotransplantation of a vital organ to a human, a non-primate generally would be a less desirable donor, in terms of phylogenetic relationship, than a primate.
The order Primates is divided into two suborders: the prosimians and the anthropoids. The anthropoids are further divided into two infraorders: the Platyrrhini, or new world monkeys, and the Catarrhini. The Catarrhini are likewise divided into two superfamilies: the old world monkeys and the hominoids. Hominoids include the great apes and humans. According to this classification scheme, the old world monkeys are more closely related to humans than are the prosimians or the new world monkeys, but not as closely related to humans as are the four genera of apes: Hylobates (gibbons), Pongo (orangutans), Gorilla, and Pan (chimpanzees).
A second very important factor in selecting a preferred xeno-species is its amenability to human handling, captive breeding, experimentation, and the like. Generally speaking, old world monkeys are much more easily maintained than are the apes.
Other important factors for an optimal xenotransplant source species include reproductive rate, body size, cost of maintenance, and anatomic and physiologic similarity to humans. The reproductive rate is a function of the average age at which individuals of the species reach sexual maturity, as well as the gestational duration, multiplicity of births, and number of reproductive years. The size of the source species is important because organs that are too small are not always suitable for transplantation into humans. Since baboons, (genus Papio) are the largest of the old world monkeys, and since their anatomic and physiologic characteristics are very similar to those of humans, they represent a desirable combination of the most important factors.
Baboons do, however, present shortcomings of their own as a genuine alternative to allotransplantation. They do not reach sexual maturity until about age 4 or 5, they typically deliver only one offspring per gestation, and they present a potential risk of transmitting erstwhile baboon pathogens to humans. All of these facts make baboons very unlike the familiar laboratory and model system animals that can be multiplied virtually at will, and that are hosts to pathogens that are relatively well known and easily controlled. For all of these reasons, creating a large colony of baboons to provide a significant supply of donor organs would be a slow and very costly process.
An even greater obstacle to the development of baboons as a useful xenotransplantation source species is that, while the most common human histo-blood group is O, baboons of group O are exceedingly rare. The resulting incompatibility of the organs of virtually all baboons with members of the largest human blood group, as discussed in greater detail below, significantly reduces the utility of present captive baboon colonies, as well as almost all baboons in the wild, as good sources of xenotransplant organs for humans as a group.
Therefore, in addition to the scarcity of suitable donor organs, compatibility considerations further limit the potential pool of donors for a particular patient. This is equally true for both allo- and xeno-organ sources.
Incompatible organs are very likely to be rejected. For example, when organs are transplanted across the ABO histo-blood group barrier, there is a high incidence of antibody-mediated rejection. One antibody-mediated form of organ rejection, known as hyperacute vascular rejection, may be quite rapid. In heart and kidney transplants, hyperacute vascular rejection has been estimated to occur in approximately 66% of ABO-mismatched cases. A second type of antibody-mediated rejection is known as accelerated rejection. In some cases of accelerated rejection, an organ recipient generates anti-donor antibodies which may then aberrantly cross react with the recipient's own cells leading, for example, to complications or death brought on by agglutination of the recipient's blood cells arising from his or her own antibodies. In addition to antibody-mediated rejection in its various manifestations, cellular rejection, associated with the cellular immune response, may also occur, albeit more slowly. Cellular rejection may be a risk even in cases where antibody-mediated rejection has been avoided or overcome. Cooper, D. K. C., Ye, Y., Niekrasz, M., Kehoe, M., Martin, M., Neethling, F. A., Kosanke, S., DeBault, L. E., Worsley, G., Zuhki, N., Oriol, R., & Romano, E. (1993) Transplantation 56:769-777 (hereinafter Cooper et al. (1993)).
Several approaches have been proposed to reduce antibody-mediated rejection, some of which may also diminish the extent of cellular rejection. A splenectomy may be performed, and may accompany pre-transplant plasmapheresis, a process that temporarily removes antibodies from the blood. However, both splenectomy and plasmapheresis may nonspecifically depress all immune responses, instead of exclusively blocking the response to ABO incompatibility alone. Cooper et al. (1993).
A more specific approach to A/B antibody removal involves passage of a patient's plasma through an affinity column that displays the specific glycans recognized by anti-A and/or anti-B antibodies. Only A/B antibodies are bound to the column while non-A/B antibodies remain in the plasma as it passes through the column. Another alternative is to competitively occupy the A/B antibodies without removing them from the plasma, by intravenously infusing small carbohydrates to which the antibodies specifically bind, thus selectively inactivating the antibodies that could otherwise mount an undesirable response to the transplanted organ. Of course, any of the above therapies may also be combined with administration of immunosuppressive drugs. Nevertheless, since A/B antibodies develop and are maintained via continuous sensitization by microbial flora in the gastrointestinal tract, the temporary removal or inactivation of A/B antibodies provides no long-term solution. Cooper et al. (1993).
Incompatibility at the histo-blood ABO locus is therefore a major determinant in limiting the suitability of a xeno- or allo-donor organ for a particular recipient. Commonly known to control a person's blood-group, the products of the ABO locus not only affect antigens on erythrocytes, but also on many other cell surfaces, including the epithelium of several important organs. Therefore, if a donor and recipient are not compatible for traditional blood transfusion because of ABO phenotype differences, they
Diamond David
Fagoaga Omar R.
Nehlsen-Cannarella Sandra
Szalay Aladar A.
Achutamurthy Ponnathapu
Knobbe Martens Olson & Bear LLP
Loma Linda University Medical Center
Tung Peter P.
LandOfFree
ABO histo-blood group O alleles of the baboon does not yet have a rating. At this time, there are no reviews or comments for this patent.
If you have personal experience with ABO histo-blood group O alleles of the baboon, we encourage you to share that experience with our LandOfFree.com community. Your opinion is very important and ABO histo-blood group O alleles of the baboon will most certainly appreciate the feedback.
Profile ID: LFUS-PAI-O-2446622