Basics in Transplant Immunology
Linda Ohler, RN, MSN, CCTC, FAAN
Robert A. Bray, PhD
I. INTRODUCTION TO THE HUMAN IMMUNE SYSTEMA. Functions of the immune system
The human body is challenged daily by millions of exogenous and endogenous threats that could cause us physiological harm unless our bodies are able to defend themselves.
The key characteristic of the immune system is that it defends us by its ability to distinguish self from nonself.
To fight off these daily threats, humans possess a complex system of defense called the immune system (Figure 2-1).
The immune system consists of highly mobile and complex cellular and soluble antibodies and chemokines/cytokines that are located throughout the body.
This complex system is comprised of cells and proteins spread throughout the body providing rapid defense against infection.
These cells are categorized as “lymphocytes” and include neutrophils, monocytes, T cells, B cells, and natural killer (NK). These are all found in the white blood cells (WBC).
Major proteins include antibodies, chemokines, cytokines, and complement proteins.
Cells located throughout the body detect foreign or nonself molecules (antigens), and when identified, immune cells are recruited to provide protection against invaders via complex immune reactions.
Throughout life, the immune system will adapt and respond to a variety of complex immune reactions or life experiences: illness, infection, pregnancy, drug exposure, or transfusions (Figure 2-2).
The immune system creates antibodies in response to these events that cause a reaction if/when the event recurs.
Over time, the lymphocytes of immune system learn to adapt and recognize self (our own tissue) versus foreign invaders (nonself).
FIGURE 2-1 The organs of the immune system.
T cells are either cytotoxic or helper cells. The T-cytotoxic cells quickly kill any signs of foreign invaders or infection, and the T-helper cells work with the B cells perform their functions.
B cells produce immunoglobulins or antibodies that turn into memory cells. These memory cells identify past infections and activate a rapid response if the infection returns. They are highly specialized cells that are able to detect self versus nonself and selectively activate only when the nonself threat is detected.
For example, vaccines are given to stimulate the T-helper cells and B cells to produce antibodies against a virus. If the body detected the virus, the immune system quickly responds to kill the virus before it can mount a significant illness.
In transplant, the new grafted organ is detected as a foreign invader (nonself), and immediately the body attempts to stimulate a response to kill it. Immunosuppressive medications are given to adapt the lymphocytes of the immune system and tolerate the new graft.
In transplant, another component of this self-recognition process is accomplished at the molecular level through a group of proteins called human leukocyte antigens (HLAs) or tissue molecules.
FIGURE 2-2 Type III immune reaction: immune complex hypersensitivity. Antigen and antibody bind together to create an immune complex. A. Systemic immune complex reaction. In systemic autoimmune reactions, immune complexes cause vasculitis and widespread tissue damage. B. Local immune complex reaction. In local autoimmune reactions, immune complexes form and cause damage to transplanted organ (e.g., antigen-antibody reaction with rejection).
The immune system provides protection by several different mechanisms designed to recognize and destroy invaders while maintaining a balance to avoid unnecessary destruction of self.1,2,3,4,5,6
Surveillance: Direct recognition of foreign antigens present on membranes of cells or microorganisms and indirect recognition of antigens presented by HLA molecules.
Defense: There are nonspecific and specific mechanisms that destroy foreign intruders and protective memory that targets particular foreign intruders to which there has been previous exposure.
Homeostasis: The capacity of maintaining a balance between the protection of self and destruction of nonself.
In transplantation, we focus on two components of an immune response associated with rejection of a transplanted organ: humoral and cellular immune responses.
The humoral immune reaction involves the production of soluble proteins (immunoglobulins), also referred to as antibodies, that bind and damage the transplanted organ. Antibodies are secreted by specialized B cells called plasma cells.
The cellular immune reaction involves interactions or communication signals between cells such as lymphocytes and antigen-presenting cells (APCs).
APCs are cells such as dendritic cells, monocytes, and macrophages.
APCs alert cytotoxic T lymphocytes of nonself antigens such as the following:
Donor kidney, liver, heart, lung, intestines, or vascularized composite tissue allotransplant (VCA).
These cytotoxic T cells evoke cellular reactions such as rejection.
Thus, when we transplant a new organ into a patient, the immune response is alerted to react against what it has determined to be nonself.
To protect the new organ from being rejected, we immediately begin to suppress the immune system with immunosuppressive medications (see Figure 2-3). See chapter on Transplant Pharmacology for additional information.
Many transplant programs start the process of suppressing the immune system with induction therapy.7
Induction therapy is the administration of an immunosuppressive agent, such as antithymocyte globulin, prior to implantation of the new organ. Induction therapy often continues for several doses during the immediate posttransplant period.
The goals of induction therapy are to delete or suppress lymphocytes and decrease the impact of an immune response that would immediately recognize the new organ as nonself.
There are many factors that can influence our ability to suppress the immune system enough to prevent recognition of the new organ.
First, the physician will select a graft that is ABO compatible without any unacceptable preformed antibodies to the recipient to prevent a hyperacute rejection immune response.
Next, the physician will select an immunosuppression regimen that will suppress the intensity of the immune response and minimize any toxic adverse effects to the recipient. Refer to the pharmacology chapter for immunosuppression strategies.
The communication system among cells is quite complex.
When cells are destroyed, cellular communication sends an alert to the bone marrow to increase production of those cells being destroyed by medication therapies.
Our principle challenge is to manage the transplant recipient in balancing the suppression of the immune system enough to prevent rejection, but not too much to increase the patient’s risk of developing an infection or malignancy.
Morbidity and mortality risks due to infection are greater than the risk of graft loss due to rejection.
Thus, we need to learn how to balance the immune system between infection and rejection.
FIGURE 2-3 Overview of mechanisms of pharmacologic immunosuppression. The molecular mechanisms by which immune cells are activated and function provide eight major points for pharmacologic intervention by immunosuppressive agents. Blockade of T-cell activation can be accomplished by (1) inhibition of gene expression, (2) selective attack on clonally expanding lymphocyte populations, (3) inhibition of intracellular signaling, (4) neutralization of cytokines and cytokine receptors required for T-cell stimulation, (5) selective depletion of T cells (or other immune cells), (6) inhibition of costimulation by antigen-presenting cells, and (7) inhibition of lymphocyte-target cell interactions. Suppression of innate immune cells and complement activation may also block the initiation of immune responses (not shown).
This chapter is designed to provide readers with a basic understanding of how the immune system functions and how we attempt to manipulate it in transplantation.
B. Types of transplants
Autotransplantation is transplantation of self-tissue.
An example would be the removal of bone marrow from an individual prior to potentially toxic chemotherapy, followed by reinfusion of the marrow back into the same individual following the medical intervention.
Another common example is for an individual to donate blood for himself/herself prior to an elective surgery.
This blood is then autotransfused into the same patient if needed during the procedure.
These transplanted tissues are not foreign; therefore, there is no risk for an immune response or antibody production.
Iso- or syngeneic transplantation refers to the transplantation of tissue or organs between genetically identical individuals, such as identical twins. Because all tissues and their proteins are genetically identical, this type of transplantation does not activate an immune response.
Allotransplantation occurs between genetically different individuals where the donor antigens will be seen as foreign (nonself) by the recipient and will trigger an immune response.
Allotransplantation is the type of transplant we will be discussing throughout this chapter.
Whether the donor is living or deceased, solid organ transplants between genetically dissimilar individuals are termed allogeneic transplants.
Allograft simply refers to a transplanted organ from an individual of the same species.
While the term allograft could refer to a bone marrow or stem cell transplant, in this chapter, we will focus on solid organ transplantation.
Currently in allogeneic organ transplantation, morbidity and mortality result mainly from infections that develop from the need to suppress the immune response to decrease the risk of rejection.
Xenotransplantation involves transplantation between biologically different species and, at this time, poses the greatest risk for rejection. In this instance, the organ is referred to as a xenograft.
This procedure is being studied by researchers as an option to help alleviate the human organ shortage.
The use of animal organs, mostly pigs or baboons, has been very controversial for a number of reasons.
While risks of rejection pose a great challenge in xenotransplantation, the risks of infections that are common in animals are of equal concern if transmitted to humans.
While this research continues with transplantation among various species of animals and demonstrates some promise, clinical trials with humans are not currently being done.
II. ANTIGEN RECOGNITION MECHANISM OF THE IMMUNE SYSTEMA. The major histocompatibility complex (MHC)
The system that is responsible for initiating and regulating immune mechanisms is known as the major histocompatibility complex.
The human MHC is located on the short arm of chromosome.6
In humans, the MHC also referred to as the human leukocyte antigen (HLA) system.
HLA antigens are proteins that reside on the surface of nearly all cells in the body and define the immunologic identity of an individual.
HLA molecules are responsible for presenting foreign proteins to the immune system.
After recognition of the foreign antigens, the immune system initiates a specific cascade of responses to destroy the foreign tissue identified.
With the development of clinical transplantation, this system has been closely studied and analyzed over the last six decades.
Human leukocyte antigens/proteins act as a genetic identification label.
The antigens are determined genetically by multiple loci (HLA-A, HLA-B, HLA-C, HLA-DR, HLA-DQ, and HLA-DP) and are inherited as a unit or haplotype: one from each parent.
Each individual possesses two haplotypes derived hereditarily from the biological parents. One set comes from the biological father and one set from the biological mother of an individual.
The diversity of HLA antigens results in an immense number of different haplotypes; thus, the probability of finding a perfect HLA match within a population is often quite low.
Within a family, the probability that a sibling will be a “perfect match” to another sibling is 1:4 or a 25% chance.10,11
Outside an individual’s immediate family, the chance of finding an identical HLA match within the general population is 1: 50,000.11
HLA antigens are not found on mature erythrocytes; this accounts for not considering HLA antigens for blood transfusions.
In addition, the rhesus (Rh) antigens are not present on lymphocytes or tissue cells, explaining why they are not taken into account for organ transplantation.
As ABO antigens are present on all cells, we ensure that the blood types are compatible between donors and recipients, but we need not be concerned with whether the Rh is positive or negative.
Nevertheless, recent clinical protocols have been implemented to allow transplantation between ABO-incompatible donors and recipients.12
Class I contains three main loci that we consider in solid organ transplantation, HLA-A, HLA-B, and HLA-C, while class II consists of multiple loci that code for HLA-DRB1, HLA-DRB3, HLA-DRB4, HLA-DRB5, HLA-DQ, and HLA-DP. Each of these loci produces individual HLA molecules or antigens.
Class I HLA antigens are expressed on the surface membranes of all nucleated cells of the human body.
Class II HLA antigens are expressed on B cells and APCs as well as on other cells of the immune system when these cells become activated.
Both class I and class II antigens trigger humoral and cellular immune responses through the presentation of small foreign peptides on the surface antigen-presenting cells to the immune system.
If a potential recipient possesses specific antibodies against a donor’s HLA antigens, she/he most likely will be excluded from consideration
for transplantation with that donor due to the likelihood of rejecting the transplanted organ.
If HLA antibodies are identified in the patient’s serum, they have been “sensitized” toward foreign HLA antigens.
The presence of preformed anti-HLA antibodies in transplant recipients leads to a higher incidence and risk of rejection.13,14
Sensitization to HLA antigens can occur following exposure to foreign tissue, during sensitizing events such as pregnancy, transfusions, or previous transplantation.12,13
Hence, screening for anti-HLA antibodies and identifying the HLA antigens of the individual through tissue typing is important for finding compatible organ transplant recipients/donor pairs, reducing rejection, and avoiding the potential for graft loss.
A complete HLA immune profile of the recipient can influence the allocation of more compatible organs for that individual, ultimately impacting the long-term success of the transplant.
B. Tissue typing
In years past, tissue typing was done with serology testing and often required 6 to 8 tubes of fresh blood.
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