Page 1134 - Clinical Immunology_ Principles and Practice ( PDFDrive )

1100 Part NiNe Transplantation

Costimulatory receptors fall into two major families, the B7 The pattern of cytokine production through the interaction
family (e.g., CD28 and CD152) and the tumor necrosis factor of the combination of signaling processes determines the nature
(TNF) family (e.g., CD154 and CD70) (Chapter 12). Although of the response, in which either cell-mediated or antibody-
several costimulatory molecule pairs have been identified, the mediated immunity is seen to dominate (Chapter 16). The T
CD28 and CD154 pathways have been the most clearly defined cells known to promote a cell-mediated response, and the
to date. CD80 and CD86 are receptor ligands on the surface of cytokines they produce, are termed T-helper 1 (Th1) cells. These
DCs and other cells that can bind to CD28 on T cells, resulting cells are associated with the production of IFN-γ. T cells promot-
in the activation of additional signal–transduction pathways ing a humoral response are referred to as Th2 and are associated
within the T cell. This has a number of effects: lowering the with the generation of IL-4, -5, and -6. Additionally, a Th17
threshold for T-cell activation; increasing glucose metabolism, population that has been identified is characterized by the produc-
12
as well as cytokine and chemokine expression, including IL-2 tion of IL-17 and promoting the infiltration of neutrophils.
production; reducing T-cell death through apoptosis; and expand- Th22 cells, which express IL-13, IL-22, and TNF-α, have also
ing the number of T cells that respond through proliferation. been described. A subset of CD4 cells called regulatory T cells
CD80 and CD86 are also linked to an inhibitory receptor, CD152 (Tregs) can also be induced following antigen exposure in the
13
or cytotoxic T lymphocyte antigen-4 (CTLA-4), which inhibits periphery (pTregs; Chapter 18). These cells secrete IL-10 or
T-cell activation possibly by competing with CD28 to bind with transforming growth factor (TGF) and have suppressive or
CD80 or CD86. CTLA-4 has a 10-fold higher receptor affinity regulatory functions against effector cells and APCs. The balance
compared with CD28 and is rapidly upregulated following T-cell of these responses results in either graft injury or the induction
activation. Additionally, CD152 activates tryptophan catabolism of tolerance (discussed below).
in DCs, which results in the inhibition of proliferation and
promotes apoptosis of the responding T cells. Related to this Memory T Cells
pathway are other pathways involving members of the B7–CD28 Following exposure to an antigen, antigen-specific memory T
family of molecules, including ICOS/B7h, PD1/PD-L1/PD-L2, and B cells are generated. These memory cells are then able to
and B7-H3. Each of these can play a role in T-cell costimulation produce a more rapid and intense immune reaction if the antigen
and later coinhibition, but for the early phase of the response, is encountered on a second occasion because they have a lower
the CD28 pathway dominates. CD40 belongs to the TNF receptor activation threshold and are less dependent on costimulation.
family, expressed on all APCs, and binds to CD154 (CD40L), Transplant recipients, particularly older patients or those who
which is present on activated CD4 cells, a subset of CD8 cells have had previous antigen exposure through previous transplanta-
and NK cells. CD40 stimulation causes triggering signals for tion, blood transfusion, or pregnancy, may therefore have specific
antibody production and induces MHC expression on APCs, anti-donor memory cells. Memory-type responses may also occur
thus amplifying antigen presentation. 11 as a result of antigen receptor cross-reactivity known as heter-
In clinical transplantation, treatment with calcineurin inhibi- ologous immunity.
tors (CNIs) to block signal 1 and/or the use of T cell–depleting
agents has been highly successful in the prevention and reversal Cell Migration
of rejection episodes. More recently, blockade of costimulatory After activation, chemotactic cytokines, or chemokines, generated
pathways has also been shown to be effective. These approaches at the site of inflammation attract leukocytes that have been
are discussed in the “Immunosuppression” section. primed in secondary lymphoid tissues to the graft (Chapter 10).
Once activated, leukocytes upregulate chemokine receptors, thus
Signal 3: Proliferation and Differentiation of enabling their migration along a chemokine gradient. Vessels in
Effector T Cells proximity to the graft become dilated, allowing increased blood
Following alloantigen recognition by the TCR–CD3 complex flow, and the endothelium becomes activated. Activated endo-
and costimulation, a process begins resulting in “signal 3.” This thelial cells externalize Weibel-Palade bodies containing P-selectin,
is the complex process involving the recruitment and phosphoryla- and chemokines generated in the graft, such as IL-8, RANTES,
tion of a series of signaling molecules, which induce intracellular and MCP-1, stick to the vascular endothelium (Chapter 11).
biochemical processes that lead to the activation of three This signals the passing leukocytes in postcapillary venules to
signal–transduction pathways: the calcium–calcineurin pathway, leave laminar flow of blood and move closer to the vessel edge
the Ras- and Rac-mitogen–activated protein kinase pathways, so that they can interact with the activated endothelial cells.
and the protein kinase C nuclear factor κB (NF-κB) pathway. Extravasation then occurs in a multistep process, involving
These pathways interact with inositol triphosphate (IP3) and molecules on the surface of activated leukocytes called Sialyl-Lewis
diacylglycerol (DAG), formed from the hydrolysis of phospha- moieties, which interact with endothelial P-selectin, forming
tidylinositol 4,5-bisphosphonate, to activate transcription factors: temporary bonds that form and break causing the leukocytes to
nuclear factor of activated T cells (NFAT), activating protein-1 “roll.” Chemokines on the endothelial surface then induce a
(AP-1), and NF-κB, respectively. These transcription factors cause conformational change in leukocyte integrin molecules, allowing
the expression of many genes leading to upregulation of growth high-affinity binding to endothelial adhesion molecules, such
factors and cytokines, in particular, IL-2 and CD25 (IL-2Rα). as intercellular adhesion molecule-1 (ICAM-1). When this occurs,
Growth signals are then delivered through the phosphoinositide- the leukocytes stop rolling, and this allows them to extravasate
3-kinase (PI3K) and mechanistic target of rapamycin (mTOR) and follow the chemokine gradient further into the graft, where
pathways to promote cell cycle progression, and initiation of damage then occurs.
clonal expansion and differentiation of activated T cells to express
effector functions. These mechanisms are targeted by various The Effector Response and Graft Destruction
immunosuppressive agents discussed in the “Immunosuppression” The immune system generates many different effector mecha-
section and illustrated in Fig. 81.5. nisms, depending both on the challenge it meets and the