Immunogenetics & Transplantation -Clinical Transplantation

Organ transplants are in widespread use. Limitations include the scarcity of donor organs and expense. Failure to achieve successful grafts is primarily due to histoincompatibility and lack of safe and effective immunosuppressive regimens to halt rejection. Avoiding transmission of infectious agents (eg, HIV, HBV, HCV, CMV) from donor to recipient requires extensive pretransplant serologic testing.

Kidney Transplantation
End-stage renal disease is the indication for kidney transplantation. Factors that determine outcome include antigenic disparity (ABO blood groups and major histocompatibility or HLA) between donor and recipient, the type of immunologic response mounted by the host, and the immunosuppressive regimen used to prevent graft rejection. Nonimmunologic factors that affect the risk of chronic rejection include age and race of recipient, donor age, length of time on dialysis, and coexisting hyperlipidemia, hypertension, or cytomegalovirus infection.

Kidneys from living related donors who are HLA-identical and also red cell ABO-matched grafts have 90% survival at 1 year; grafts from less-well matched relatives and from living unrelated donors have lower rates. Antigens are matched for HLA-A, -B and -DR loci, with -DR compatibility most important for long-term graft survival. Grafts from cadaver donors with zero HLA mismatches have a half-life of 11.3 years. Those with six mismatches have a half-life of 6.8 years, compared with those from HLA-identical siblings, which have a half-life of 23.6 years.

Some donors are highly sensitized to HLA antigens from previous transfusions, ie, possess high panel reactive antibody levels. It may be difficult to find a suitable donor, since a positive cross-match by cytotoxicity testing is likely and would be a contraindication to transplant. Donor screening is performed in all cases to assess suitability, rule out hypertension or anatomic anomalies, and avoid transmission of hepatitis viruses, HIV, and other infectious agents. Owing to the scarcity of related donors, living unrelated donors may be used in certain circumstances. Pretreatment of recipients with blood transfusions from the donor appears to extend graft survival even longer.

Delayed allograft function can be due to hyperacute graft rejection, post ischemic acute tubular necrosis, cyclosporine toxicity, or obstructive nephropathy. If conservative measures do not improve function or patients are at high risk of allograft rejection, renal biopsy should be performed for definitive diagnostic purposes. Renal allograft rejection may be due to hyperacute rejection from binding of cytotoxic antibodies and complement activation, acute rejection from cellular immune responses, or chronic rejection. A form of interstitial nephritis secondary to polyomavirus infection is associated with aggressive immunosuppression.

Chronic allograft nephropathy is characterized by vasculopathy and immune-mediated graft obliteration. Previous acute rejection is strongly linked with later chronic rejection, and severity of those episodes has prognostic implications. Cyclosporine-induced nephrotoxicity and recurrent or de novo renal disease are also significant factors affecting long-term survival.

High-Dose Chemotherapy with Hematopoietic Progenitor Cell Transplantation

Transient myelosuppression after cancer chemotherapy is a well-established adverse effect of such treatments. For most regimens, it is rapidly reversible and requires no intervention. Some malignancies (eg, many leukemias, lymphomas, and chemotherapy-sensitive breast and small-cell lung carcinomas) may demonstrate a higher cure rate with higher-dose therapy; however, associated with this approach is an increase in hematologic toxicity. Administering the maximal tolerated chemotherapy dose and restoring all hematopoietic functions as rapidly as possible has led to evolution of the concept of hematopoietic progenitor cell (HPC) or “stem cell” transplant. HPC transplants have also expanded somewhat into the therapy of certain nonmalignant disorders of hematopoiesis and hematologic function; examples are aplastic anemia, sickle cell anemia, thalassemia, myelodysplasia, amyloidosis, and paroxysmal nocturnal hemoglobinuria.

The sources of HPC are the bone marrow, peripheral blood, and cord blood. They comprise less than 0.5-1% of all nucleated bone marrow cells. It has become common practice to harvest HPCs from the peripheral blood by apheresis. As the peripheral blood has approximately one-fortieth the number of circulating HPCs as the bone marrow, these cells must be “mobilized” by the administration of cytotoxic chemotherapy (with the harvest being performed during the recovery phase) or enriched by the administration of hematopoietic growth factors. The cells are frozen and administered at a later date. Transplantation of HPC from umbilical cord blood can be used in unrelated donors, with a potentially lower rate of graft-versus-host disease, or may be autologous, from frozen stored blood.

Because syngeneic transplants between identical (monozygotic) twins are rare, the two predominant transplants are autologous, where the HPCs are harvested from and returned to the patient; or allogeneic, where the source is an HLA-matched donor, ideally a sibling. The goals of the two procedures -  and their associated adverse effects -  are frequently different. Allogeneic transplants are most commonly offered to patients with malignant and nonmalignant disorders involving the bone marrow. Chemotherapy is given to ablate the marrow, resulting in maximal suppression or eradication of the recipient’s native immune system. The bone marrow is repopulated by infusion of donor cells containing not only HPCs but also functional donor T lymphocytes. These T cells can cause graft-versus-host disease, in which the recipient’s tissues are recognized as nonself. While this is occasionally desirable, as in the “graft-versus-leukemia” effect, it is the cause of considerable morbidity and can be fatal. There are two separate phases of graft-versus-host disease: acute, secondary to cytokine-mediated cytotoxicity against the cells of the liver, the mucosa of the gastrointestinal tract, and skin; and chronic, characterized by fibrosis and collagen deposition and resembling autoimmune disease such as scleroderma. The incidence of graft-versus-host disease can be decreased by depleting the donor marrow of T cells, but this is associated with a higher incidence of graft failure and, in the case of leukemia, a higher relapse rate. Allogeneic peripheral HPC transplants have been attempted, and graft-versus-host disease in such cases does not appear to be as severe.

Autologous HPC transplants are performed solely for the treatment of malignancies. In these cases the chemotherapy is intensively myelosuppressive though not necessarily myeloablative. One prominent exception is patients with chronic myelogenous leukemia in blast crisis, who receive their autologous HPC in an effort to return their disease to the chronic phase. Since patients usually have some residual immune function and are receiving their own HPC -  and thus do not require post transplant immunosuppression -  the risk of opportunistic infections and immunosuppression-related neoplasia is markedly reduced.

The success rates of HPC transplantation depend mostly upon the underlying disease and the associated risk of relapse (in cases of leukemia), the level of matching between donor and recipient (and thus the likelihood of graft-versus-host disease), the age of the recipient, and the complications associated with conditioning (veno-occlusive liver disease and infection). Overall, the survival rates at 1 year are about 60-70% in aplastic anemia and 40-75% in various forms of leukemia and other neoplasms such as non-Hodgkin’s lymphomas; results in breast carcinoma are less well defined.

Bhatia V et al: Novel approaches to allogeneic stem cell therapy. Expert Opin Biol Ther 2001;1:3.

Champlin RE et al: Blood stem cells compared with bone marrow as a source of hematopoietic cells for allogeneic transplantation. IBMTR Histocompatibility and Stem Cell Sources Working Committee and the European Group for Blood and Marrow Transplantation (EBMT). Blood 2000;95:3702.

Erlich HA et al: HLA DNA typing and transplantation. Immunity 2001;14:347.

Gyger M et al: Immunobiology of allogeneic peripheral blood mononuclear cells mobilized with granulocyte-colony stimulating factor. Bone Marrow Transplant 2000;26:1.

Hariharan S: Long-term kidney transplant survival. Am J Kidney Dis 2001;38(6 Suppl 6):S44.

Nankivell BJet al: The natural history of chronic allograft nephropathy. N Engl J Med 2003;349:2288.

Provided by ArmMed Media
Revision date: July 3, 2011
Last revised: by David A. Scott, M.D.