Page 1135 - Clinical Immunology_ Principles and Practice ( PDFDrive )

CHaPter 81 Concepts and Challenges in Organ Transplantation 1101

microenvironments that are present. In transplantation, the type mediators, such as TNF-α. Perforins insert into the target cell
of transplanted tissue, graft site, and immune status of the membrane to form pores, allowing granzyme to enter the cell,
recipient at time of transplantation may modify this response. and this causes proteolysis and activates the caspase cascade. Fas
Although initiation of rejection in a nonsensitized recipient is ligand binds to Fas on the target cell and also initiates the caspase
principally T-cell dependent, many components of the immune cascade. These processes induce target cell apoptosis and acute
system contribute to the subsequent destruction of the trans- cellular rejection and typically occur 1 week to 3 months after
planted tissue. Graft destruction may be alloantigen specific, or transplantation.
there may be bystander tissue destruction. The nature of the Additionally a nonspecific delayed-type hypersensitivity
immune cells involved in the effector response is reflected in the response occurs, usually mediated by CD4 cells that are attracted
characteristics of the resulting damage and in the speed of onset to the graft and involving the release of multiple proinflammatory
of tissue destruction. cytokines, including IL-1, IFN-γ, and TNF-α. This leads to the
recruitment and activation of further leukocytes, affects graft
Acute Antibody-Mediated Rejection cell permeability and vascular smooth muscle tone, thus affecting
Alloantigen-specific antibodies, or alloantibodies, are secreted graft physiology and contributing to acute and chronic rejection.
by plasma cells. Alloantibodies are produced after alloantigen- CD4 alloreactive T cells responding to donor-derived peptides
driven B-cell activation in the presence of T-cell help, such as bound to recipient MHC class II molecules have also been cor-
can occur during rejection or following a blood transfusion. related with chronic allograft dysfunction. 15
Antibodies that cross-react with alloantigens can also be generated As acute allograft rejection is initiated by the recognition of
as a result of infections that result in heterologous immunity. polymorphic donor MHC molecules by recipient T cells, it follows
In the former, in addition to DCs, the B cells themselves may that transplantation of MHC incompatible tissues will elicit a
act as APCs. MHC class II molecules are presented to and bind strong, T cell–dependent immune response to donor tissues.
immunoglobulins (Igs) on the surface of B cells, enabling the B In general, mismatches for only class I MHC result in slower
cell to internalize the alloantigen and process it into peptides rates of rejection compared with grafts with differences in
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that are presented at the cell surface within MHC class II molecules class II MHC or both class I and II. Rejection can still
(Chapter 6). The subsequently activated T cells produce cytokines occur when transplantation has taken place between MHC-
that activate B cells enabling them to differentiate into matched siblings because of T-cell recognition of minor histo-
alloantibody-producing plasma cells. When allospecific antibodies compatibility antigens.
encounter their specific antigen, antibody-mediated rejection
occurs. Antibodies function through a number of effector Delayed Allograft Rejection and Dysfunction
mechanisms. Antibody binding activates endothelial cells within Rejection later after transplantation, which is often referred to
the graft, resulting in the expression of adhesion molecules, as chronic rejection or chronic allograft dysfunction, comprises
cytokines, and chemokines as well as the synthesis of tissue factor. a number of mechanisms. It is characterized by a cellular infiltrate
Antibody binding can trigger complement activation, which can constituted of macrophages, eosinophils, NK cells, and T cells,
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result in cell lysis and graft damage directly or indirectly by the where the primary target is the vascular endothelium. Damaged
binding of complement components to the graft and the recruit- endothelium allows platelet deposition on the arterial wall and
ment of macrophages and neutrophils. Additionally damage is growth factor production. This, in turn, leads to smooth muscle
caused by a mechanism whereby effector cells, such as NK cells proliferation in the arterial wall media. Proliferating muscle cells
and macrophages, bind to the Fc non–antigen-specific portion invade the intima and contribute to intimal fibrosis. These changes
of the antibody. This encourages NK cells and macrophages to are concentric, affecting all graft arteries. In heart transplants,
kill any target cells with antibody bound to their surface. This this may appear as transplant arteriosclerosis. Chronic rejection
is a nonspecific process termed antibody-dependent cellular therefore manifests in an organ-specific manner. For example,
cytotoxicity (ADCC) and can contribute to graft rejection. 14 within renal glomeruli glomerulosclerosis and interstitial fibrosis
When donor-specific alloantibodies (DSAs) exist in a recipient may develop, whereas in lungs, bronchiolitis obliterans develops.
prior to transplantation (e.g., as a result of previous transplanta- The underlying mechanistic processes remain similar.
tion, blood transfusion, or pregnancy), a dramatic response is
seen upon perfusion of the transplanted graft. Coagulation and Clinical Implications
complement cascades are activated, resulting in extensive To prevent hyperacute rejection, patients on transplant waiting
thrombosis and graft infarction within minutes. This so-called lists are monitored routinely for the development of anti–human
hyperacute rejection is now very rarely seen in clinical practice leukocyte antigen (HLA) antibodies as a marker of sensitization.
because of the advances in screening and cross-matching tech- Immediately before transplantation, a further check is performed
niques as well as desensitization techniques, such as plasmapheresis by mixing recipient serum and donor splenocytes and observing
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and intravenous immunoglobulin (IVIG). for cell lysis. The extent of the risk of hyperacute rejection is
determined by the antibody target and quantitative titer of the
Acute Cellular Rejection anti-donor antibodies. Highly sensitized recipients can remain
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As described above, following the non–antigen-specific innate on waiting list for extended periods but may have successful
response to organ retrieval and implantation, an inflammatory transplantations after desensitization, as mentioned previously,
environment is created within the graft, thus promoting an by removal of existing antibodies through plasma exchange or
adaptive cellular response over the ensuing days. Naïve cytotoxic adsorption or by depletion of B cells with immunosuppressive
T cells, activated by CD4 cells clustering with APCs, migrate to agents, such as rituximab or proteasome inhibitors. Despite the
the graft, where they recognize allogeneic class I MHC molecules. extensive screening performed to detect donor HLA antibodies
This causes them to release cytotoxic molecules, such as perforin before transplantation, preformed antibodies against donor
and granzyme B; upregulate surface Fas ligand; and secrete soluble non-MHC antigens may exist and have the ability to induce