Xenotransplantation Science, Ethics, and Public Policy (1996) / Chapter Skim
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2. Assessing the Science Base
2. Assessing the Science Base
Pages 17-38
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From page 17... ...
The immunological response to a xenograft depends, in part, on the phylogenetic distance between the source animal and the host. Transplants between closely related species (e.g., example, humans and nonhuman primates or rats and guinea pigs)
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From page 18... ...
STAGES OF THE IMMUNE RESPONSE The immunological response to an organ xenograft can be divided into different phases, although the division is to some extent arbitrary, both because the manifestations of one can continue into, or be present in, another and because they can occur as a continuum. The first phase, hyperacute rejection,
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From page 19... ...
If Hyperacute rejection is avoided, then the graft is rejected after a period of some days by a process known as delayed xenograft rejection (also referred to as acute vascular rejection) , which begins within hours and results in rejection after several days (Table 2-1~.
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From page 20... ...
Hyperacute rejection is not a factor in cellular xenografts, such as transplants of pancreatic islet cells, because such grafts are revascularized by the recipient; thus, the endothelial cells are self (i.e., not "foreigner. If Hyperacute rejection is prevented by depleting xenoreactive antibodies or blocking complement in the recipient, then the graft survives to experience delayed xenograft rejection.
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From page 21... ...
What is known about chronic rejection comes from the study of allografts, primarily because discordant xenografts have not remained viable long enough to meet with chronic rejection. Progress in Molecular and Cellular Biology Much scientific progress has been made in defining the molecular basis of hyperacute and delayed xenograft rejection, the first and second phases of the host immune response to a discordant organ xenograft.
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From page 22... ...
Pathology studies using markers that bind to IgM have identified IgM antibodies along endothelial cell surfaces of xenografts; depletion of serum IgM antibodies before transplantation prevents hyperacute rejection. Recent studies have identified the specific target (epitope)
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From page 23... ...
Another complement protein causes changes in the structural integrity of endothelial cells, which leads to gaps in the endothelial surface and subsequent edema and hemorrhage (Platt et al., 1990~. The critical role of antibody binding with subsequent complement activation in hyperacute rejection is supported by experiments in which either xenoreactive antibody or complement is depleted prior to xenotransplantation.
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From page 24... ...
T-cellmediated rejection is characterized by gradual loss of graft function brought about by a cellular immune response. Host immune cells react with a variety of graft cells, including vascular endothelial cells and parenchymal cells.
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From page 25... ...
MHC Class I molecules are found on all mammalian nucleated cells, but Class II molecules are expressed on only a few cell types: endothelial cells and immune cells such as B-cells, dendritic cells, monocytes, and macrophages. Accordingly, a graft possesses MHC Class I molecules on all of its cells, but MHC Class II molecules are present only on endothelial cells in its blood vessels and on its passenger leukocytes, which are immune cells residing in any tissue.
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From page 26... ...
. These medications attenuate or slow the immune reactions responsible for rejection, although all too frequently they do not completely abolish them since acute rejection episodes and chronic rejection still occur.
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From page 27... ...
The major obstacle to solid organ discordant xenografts is hyperacute rejection, as discussed above, which cannot be overcome with immunosuppression. Clinical experience with xenografts is so limited that it is difficult to forecast the effectiveness of existing immunosuppressives in combating immune rejection.
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From page 28... ...
Applied in human clinical allotransplant trials Can result in graft-versus-host disease caused by action of T-lymphocytes Recent work promising with facilitating cells and removal of T-cells Possible use of mixed (donor and host) bone marrow chimerism to decrease risks
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From page 29... ...
Class I antigens were selected for antibody masking because of their expression on islet cells and because of the sparse expression of other epitopes such as ICAM-1 and LFA-3, which on other cell types promote adhesion between host cells and the graft. It was not necessary to mask epitopes responsible for hyperacute rejection, because the islet and liver cells were nonvascularized and, as such, eventually carried endothelial cells of the host.
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From page 30... ...
Source animal modification is also feasible, although far more difficult, for whole organs (Faustman, 1995~. Not only do whole organs contain a multiplicity of cell types with a variety of antigenic determinants, but organs also contain vascular endothelial cells foreign to the recipient and, thus, are complicated by hyperacute immune rejection.
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From page 31... ...
An alternative approach to blocking hyperacute rejection is by abolishing expression of the galoc(1-3) gal epitope that is recognized by preformed antibodies in the host on the graft endothelial cells, an idea proposed by Sandrin McKenzie and colleagues (McKenzie et al., 1995)
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From page 32... ...
When gene knockouts are developed for these other species, it would permit, for example, inactivation of the gene encoding the enzyme that is responsible for forming the antigenic epitope on surface glycoproteins, thereby potentially blocking hyperacute rejection. Tlymphocyte-mediated rejection could perhaps be avoided by disabling the set of genes encoding Class I or II MHC antigens.
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From page 33... ...
Modification of the Host Bone Marrow Chimerism Bone marrow chimerism represents another strategy to circumvent the immune response in either allotransplantation or xenotransplantation (Ildstad, 19959. The strategy calls for bone marrow to be transplanted into a host along with a solid organ from the same donor or source animal, or from a second donor carrying the same antigens as the first.
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From page 34... ...
It can occur either in bone marrow transplants alone or in combination with organ transplants using either allogeneic or xenogeneic tissue. Graft leukocytes initiate an immune response that rejects host tissues, most commonly skin, gastrointestinal tract, and liver.
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From page 35... ...
To produce a functioning immune system, transplanted bone marrow cells must mature, and some of the mechanisms of this process have been discovered. It appears that some bone marrow cells from the source or donor, known as stem cells, migrate to the host's thymus, the normal site of development of certain immune cells.
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From page 36... ...
The application of bone marrow chimerism to solid organ discordant xenografts would require additional steps to circumvent hyperacute rejection. In summary, establishment of bone marrow chimerism represents a highrisk, high-reward strategy for whole organ allografts and, potentially, xenografts.
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From page 37... ...
Once mutual tolerance occurs, immunosuppression should in theory no longer be necessary. To promote microchimerism, these and other investigators are infusing bone marrow cells at the time of whole organ transplant in ongoing clinical trials.
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From page 38... ...
Success with glucose regulation in allograft animal models has led to human clinical trials, in which islets from human cadavers were microencapsulated in hollow fiber devices and implanted into nonimmunosuppressed diabetic patients (Scharp et al., 1994~. Over the course of the two-week-long safety trial, no complications were recorded and 90 percent of the encapsulated cells survived.
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