Immunsuppressive Agents Corticosteroids Calcineurine Inhibitors Antiproliferative Agents Monoclonal Antibodies Polyclonal Antibodies Side Effects
Immunotherapy Inductive Therapy Maintenance Therapy Episodic Treatment
Current Areas of Research New Drugs Drug Efficacy Alternative Therapies Tolerance Tissue Engineering Xenotransplantation Glossary of Terms References
|Healthy islets (center) surrounded by non-insulin producing pancreatic cells.|
|Hyperacute rejection in progress: Islets (center) are being filtrated as part of immune system attack.|
Hyperacute rejection occurs usually within the first 24 hours after transplantation.
This response occurs so quickly that the tissue never becomes vascularized.
It is characterized by thrombotic occlusions and hemorrhage of the graft
vasculature that begins minutes to hours after the graft is placed. Hyperacute
rejection is caused by preexisting host antibodies that bind to antigens
present in the graft endothelium.
Antigen recognition activates the complement
system. There is also an influx of neutrophils.
Endothelial cells and platelets are also induced to shed lipid particles
from their membrane that promote coagulation.The resulting inflammation
prevents vascularization of the graft. The graft then suffers irreversible
damage from ischemia.
There are several explanations for the preexisting antibodies that initiate
hyperacute rejection. Recipients of blood transfusions sometimes develop
antibodies to MHC antigens from the transfused blood. If some of these
antigens match those in a graft, then hyperacute rejection may result.
Multiple pregnancies may also expose the woman to the paternal antigens
of the fetus, resulting in the creation of antibodies. Finally, prior
recipients of transplants may have already formed antibodies to other
MHC antigens, so they may be present at the time of a second transplant.
Most of the time hyperacute rejection can be avoided by screening for
Acute rejection usually begins after the first week of transplantation, and most likely occurs to some degree in all transplants (except betweenidentical twins). It is caused by mismatched HLA antigens that are present on all cells. HLA antigens are polymorphic therefore the chance of a perfect match is extremely rare. The reason that acute rejection occurs a week after transplantation is because the T-cells involved in rejection must differentiate and the antibodies in response to the allograft must be produced before rejection is initiated. These T-cells cause the graft cells to lyse or produce cytokines that recruit other inflammatory cells, eventually causing necrosis of allograft tissue. Endothelial cells in vascularized grafts such as kidneys are some of the earliest victims of acute rejection. Damage to the endothelial lining is an early predictor of irreversible acute graft failure. The risk of acute rejection or an is highest in the first 3 months after transplantation, and is lowered by immunosuppressive agents in maintenance therapy. The onset of acute rejection is combatted by episodic treatment.
Chronic rejection is a third type of rejection and occurs months to years following transplantation. It is characterized by graft arterial occlusions, which results from the proliferation of smooth muscle cells and production of collagen by fibroblasts. This process, termed accelerated or graft arteriosclerosis, results in fibrosis which can cause ischemia and cell death. These fibrous lesions occur without evidence of an overt cause (such as vascular injury or infection), although it is hypothesized that chronic rejection is really the result of continued prolonged multiple acute rejections. This hypothesis is based on the knowledge that the resulting fibrosis is similar to the fibrosis that accompanies natural healing of a wound. Now that there are treatments for acute rejection, chronic rejection is the major cause of graft loss. Most recipients must take immunosuppressive drugs for the rest of their lives, and even that may not be enough to combat chronic rejection. This poses a dilemma in the trend of immunotherapy, since immunosuppression is highly focused to prevent acute rejection and does not substantially address chronic rejection mechanisms. Therefore, alternative therapies such as tissue engineering, tolerance, and xenotransplantation attempt to bypass the perils of chronic rejection and rejection overall.
|This graph shows pancreas graft survival rates of three types of cadaveric grafts. At three years rejection is still a concern, as only about 60-80% of grafts are still functioning at this point.|
Acute vascular rejection is found during transplantation of xenografts. Even though initial hyperacute rejection is avoided in discordant species through transgenic and knock out techniques in gene recombination, acute vascular rejection still occurs 4-8 days after transplantation. This form of rejection is characterized by endothelial activation and coagulation, causing cell damage, thrombosis and eventual graft rejection. Although it occurs more slowly than in hyperacute rejection, the end result of transplant failure is the same. It is also unclear as to whether complement is a part of the pathways of acute vascular rejection. There is some evidence that suggests that it is caused by returning or residual anti-alpha-gal antibodies, which target the alpha-gal antigen found on pigs and other species. Acute vascular rejection is the main barrier to xenografts, and research is attempting to circumvent this new phenomena of rejection; however, currently even with heavy immunosupression, most pig to primate grafts fail within thirty days due to acute vascular rejection.