By Ramsey Hachem, M.D.
Washington University School of Medicine Barnes-Jewish Hospital
Division of Pulmonary and Critical Care
August, 2010
Human leukocyte antigens (HLA) are proteins on cell membranes that are critical to the immune response. After an infection, immune cells known as antigen presenting cells engulf bacteria and display parts of them on their outer cell membrane on HLA proteins. Cells of the adaptive immune system can then recognize pieces of bacteria but only in the context of the HLA molecule. In other words, the HLA molecule is necessary for the adaptive immune system to recognize and respond to infections. Similarly, when viruses infect cells, some of their peptides are displayed on the surface of infected cells on HLA molecules. This signals immune cells to recognize that the cell is virally infected and these kill the infected cell to limit the viral replication. There are several different HLA molecules and each can have one of multiple alleles. Indeed, the possible combinations are very numerous because there is significant variability in the structure of each HLA, and the specific combination is unique to an individual.
Antibodies are proteins made by the immune system to identify and neutralize foreign substances, such as bacteria or viruses. After encountering a foreign molecule, the immune system makes antibodies that are very specific for this molecule. This allows the immune system to respond rapidly and vigorously the next time it encounters this molecule. Some people develop antibodies directed against certain HLA after an exposure to different, or “non-self”, HLA molecules. The most common exposures to non-self HLA molecules are blood transfusions, organ transplantation, and pregnancy. Clearly, not everyone develops antibodies after a blood transfusion or pregnancy, and the reasons why one individual develops antibodies and another doesn’t are poorly understood. People who have circulating antibodies directed against certain HLA are typically called “sensitized”. Nonetheless, these antibodies are of little significance outside of transplantation. At the time of transplantation, the immune system will be exposed again to non-self HLA molecules on the donor organ, and if one of these was previously encountered after a blood transfusion or pregnancy, the patient may have antibodies directed specifically against that molecule. These can then bind to their specific target (the HLA molecule) and activate an immune cascade that results in very rapid and severe tissue injury. This is known as hyperacute rejection and seriously jeopardizes the viability of the transplant.
Fortunately, hyperacute rejection is an uncommon problem today because patients are screened for the presence of anti-HLA antibodies before transplantation. If anti-HLA antibodies are detected, the standard approach has been to avoid donors with the reactive HLA. However, some patients may have numerous anti-HLA antibodies or antibodies to very common HLA molecules. The acceptable donor pool becomes substantially smaller for these highly sensitized patients. This results in a lower likelihood of having a transplant and a longer waiting time for the transplant. For patients with end-stage lung disease, this increases the risk of death while waiting for a transplant.
An alternative approach to avoiding donors with the reactive HLA is depleting or neutralizing circulating antibodies before transplantation. This therapy is known as desensitization and has been used primarily in kidney transplantation because a considerable proportion of patients with end-stage kidney disease are sensitized. Numerous combinations of treatments have been used to deplete circulating antibodies with variable results. A cornerstone agent in many of these combinations has been intravenous immune globulin (IVIG). Its mechanisms of action are not completely understood but appear to include inhibiting activation of the immune cascade after antibody binding to the HLA molecule, neutralizing anti-HLA antibodies, and inhibiting other immune cell activation. Recently, a small study in kidney transplantation reported adding a chemotherapy drug called rituximab to IVIG to desensitize patients waiting for an acceptable donor. Rituximab binds to a specific molecule on B cells and results in prolonged B cell depletion. This seems to have a synergistic effect when combined with IVIG, and the combination can reduce antibody levels effectively. In the recent kidney study, 16 of the 20 patients treated with this regimen were able to have a transplant. However, these kidney recipients had a higher than usual incidence of rejection although there was only one graft failure during the first year after transplant.
While this experience is encouraging, desensitization has not been studied carefully in lung transplantation. It is well known that the incidence of rejection after lung transplantation is higher than after kidney transplantation, and the impact of more frequent and perhaps more severe rejection episodes on graft survival may be ominous. Nonetheless, a thorough evaluation of desensitization in lung transplantation is essential to overcoming this barrier.