By Ramsey Hachem, M.D.
Washington University School of Medicine Barnes-Jewish Hospital Division of Pulmonary and Critical Care
October, 2006
The adaptive immune system responds to pieces of foreign proteins that are presented to immune cells known as lymphocytes. Specialized immune cells known as antigen presenting cells engulf invading or foreign substances, including bacteria, process them, and present them to the lymphocytes, and this stimulates a vigorous immune response. This mechanism is very specific; the antigen presenting cells display foreign peptides in the groove of a class of cell surface molecules known as the major histocompatibility complex proteins or human leukocyte antigens. Lymphocytes can only recognize the piece of foreign protein when it is presented in the context of major histocompatibility complex proteins on antigen presenting cells. Some invading organisms, such as viruses and certain bacteria, live inside the host’s cells and are called intracellular. These organisms display their proteins on the surface of the cells they invaded in the grooves of major histocompatibility complex proteins. Another class of lymphocytes recognizes the presented proteins as foreign, signifying that the cell presenting these proteins has been infected, and kill the infected cell to limit the invading organism’s ability to replicate.
In the 1950’s, it was recognized that many people, especially those who have received blood transfusions or had been pregnant, had antibodies, or circulating immune proteins, in the serum that reacted against cell surface proteins of other people. These cell surface proteins were called human leukocyte antigens (HLA), a term that is synonymous with major histocompatibility complex proteins. It was then recognized that HLA proteins could be the targets of the immune response after organ transplantation. In kidney transplantation, matching donor and recipient HLA proteins leads to a lower rate of rejection and better graft survival. However, HLA matching between recipients and donors has not been done in lung transplantation because of time limitations. In addition, studies evaluating the impact of the number of HLA mismatches between recipients and donors after lung transplantation have been inconclusive. Nonetheless, patients who have developed antibodies directed to certain HLA proteins before transplantation require special consideration.
These, so called sensitized patients, typically develop antibodies to HLA proteins after a blood transfusion, pregnancy, or a previous organ transplant. Multiparous women are particularly prone to develop antibodies to HLA proteins. Their development is insignificant unless the patient is to receive an organ transplant. In the setting of organ transplantation, if the patient receives an organ from a donor with the HLA proteins that they have developed antibodies against, there is considerable risk of hyperacute rejection, which typically manifests as immediate graft dysfunction and often results in graft failure. Therefore, there are generally two approaches for the sensitized patient awaiting organ transplantation. The most common approach is to wait for an organ from a donor who does not have the HLA proteins that the recipient has antibodies directed against. Obviously, this limits the potential donor pool and usually prolongs the waiting time. The alternate approach is to try a desensitizing regimen, which attempts to remove the preformed antibodies and stop their production. Unfortunately, this has sometimes been impossible despite a combination of treatments including plasmapheresis, intravenous immunoglobulin, and some immunosuppressant to stop the production of antibodies. In addition, even if the preformed HLA antibodies are removed from the circulation, the risk of reemergence of the antibody after transplantation is always present and may jeopardize the outcome.
After transplantation, recipients may develop antibodies to the HLA proteins of the donor de novo. This late development of antibodies to HLA proteins has been consistently associated with recurrent or persistent acute rejection and chronic rejection after lung transplantation. It is thought that this represents a direct immune response to the donor organ and highlights the importance of the humoral immune response in transplantation. Unfortunately, the usual immunosuppressive regimen, such as cyclosporine, tacrolimus, azathioprine, and prednisone, does not suppress antibody formation adequately, and other regimens may be necessary. The potential options include plasmapheresis, which removes the antibodies from the circulation, intravenous immunoglobulin, which binds and inactivates the antibodies, and mycophenolate mofetil and rituximab, which can suppress the formation of additional antibodies. However, it is not clear if inactivating or removing the antibodies from the circulation has a favorable impact on acute or chronic rejection. This is the focus of ongoing investigation and the optimal regimen is yet to be identified.