**2.1. Dendritic cells (Figure 2)**

compatibility at the level of polymorphic amino acid triplets or eplets in antibody-accessible regions, and the benefit of acceptable HLA-mismatch programs in improving the transplant

Immune protection against foreign antigens in humans relies on a coordinated response of both innate and adaptive immune system [1]. The innate system, comprising of anatomical barriers (e.g. skin), phagocytic cells (e.g. macrophages), and soluble compounds (e.g. comple‐ ments and interferons [IFN]) provide an efficient initial defence against foreign antigens such as donor antigens in solid organ transplantation but this response lacks specificity. In contrast, subsequent adaptive immune response has the ability to create a large diversity of antigenspecific responses upon antigenic challenge to the host, with the development of immunolog‐ ical memory consequent on subsequent exposure to the same antigen. This response involves predominantly lymphocytes and antibodies, and is characteristically more intense, leading to

> **Foreign Antigens (donor-derived MHC peptides)**

**The ability of dendritic cells to coordinate innate and adaptive immune system.** Upon exposure to foreign anti‐ gens, dendritic cells secrete pro-inflammatory cytokines ± cell-cell contact, activate effector cells including natural kill‐ er cells and macrophages (innate immunity). Immature dendritic cells capture and process antigens for presentation to T cells via major histocompatibility complexes. DC undergo maturation and migrate to secondary lymphoid tissues (enhanced by inflammatory cytokines produced by natural killer cells and CD40 ligand expressed by activated T cells). Mature dendritic cells drive the expansion of antigen-specific, major histocompatibility complex-restricted T and B cell

potential of highly sensitized transplant candidates.

a more rapid elimination of the foreign antigen (Figure 1).

responses and the development of immunologic memory (adaptive immunity).

**Figure 1.** Innate and adaptive immune response to foreign antigens.

**2. Basic transplant immunology**

346 Current Issues and Future Direction in Kidney Transplantation

Dendritic cells (DC) are a group of rare, heterogenous population of professional antigenpresenting cells (APC) that can initiate primary immune responses, and hence have the ability to regulate both innate and adaptive immune responses [2-4]. Precursor DC (pre-DC), arising from bone marrow progenitors, enter tissues as immature DC with superior phagocytic capabilities. DC encounter foreign antigens such as donor antigens (in solid organ transplan‐ tation), bacteria and tumour antigens resulting in the secretion of cytokines (e.g. IFN) and activation of natural killer (NK) cells, macrophages and eosinophils. Following antigen capture and processing, DC undergo maturation and migrate to secondary lymphoid tissues where they present processed antigen/peptide coupled to major histocompatibility complexes (MHC) to T cells, allowing for selection and expansion of antigen-specific cluster designation (CD)4+ T-helper cells. These CD4+ T-helper cells subsequently amplify the immune responses by regulating antigen-specific (e.g. CD8+ cytotoxic T cells, B cells), and antigen non-specific (e.g. macrophages, NK cells, and eosinophils) effector cells.

**Overview of the complex relationship between dendritic cells and effector T and B cells.** Immature DC (MDC and PDC) maturate in response to appropriate stimuli (e.g. microbial products, TLR ligands). Mature DC secretes immunor‐ egulatory cytokines (including IFN-α and IL-12] and with cell-cell contact, modulates effector cell response including NK cells, B and T cells as well as providing a positive feedback to DC to initiate ongoing activation and maturation. Activated effector cells could in turn modulate DC activation, maturation, and survival as well as enhancing other ef‐ fector cell functions through the production of cytokines (IFN-γ) and/or via cell-cell contact.

**Figure 2.** Interaction between dendritic cells and effector T and B cells.

DC play a critical role in the initiation and regulation of adaptive T cell responses, the main‐ tenance of central and peripheral tolerance in normal steady-state and hence are essential in regulating immune responses in solid organ and cellular transplantation. DC have dual roles in organ transplantation. They are responsible for allorecognition and presentation of foreign antigens to T cells, which may initiate allograft rejection; but are also involved in the promotion of transplant tolerance.

chronic rejection [16]. In contrast, recipient's DC may acquire allogeneic donor antigens following migration into the allograft in response to proinflammatory cytokines and chemo‐ kines. Recipient's DC present donor MHC-derived peptides (e.g. regions of MHC class II molecules) loaded to self-MHC molecule to recipient's T cells. This mode of presentation is termed *indirect allorecognition* and may be more important in establishing chronic rejection. Unlike direct allorecognition, indirect allorecognition involves a less potent T cell response with a reduced proportion of recipient's T cells involve in the immune response directed against the donor-derived antigens [17, 18]. The finding of a higher frequency of T cells with indirect anti-donor reactivity in transplant recipients with established chronic rejection support this finding [16]. Similarly, studies in non-human primates demonstrated that inhibition of direct anti-donor reactivity can prolong graft survival, but does not prevent late graft loss to chronic rejection [19]. In both direct and indirect allorecognition pathways, DC can internalise extracellular donor antigens, process them and present them to either CD4+

The Evolution of HLA-Matching in Kidney Transplantation

http://dx.doi.org/10.5772/54747

CD8+ T cells through MHC class I or II molecules respectively. However, the contribution of direct and indirect pathway in acute and chronic allograft rejection remains controversial with studies demonstrating that indirect pathway may also be important in the initiation of acute

Following activation of naïve T cells, activated CD4+ T cells proliferate and differentiate into different cell types with distinct cytokine profiles. Subtypes of helper T cells include type I helper T (Th1], Th2 cells, Th17 cells and regulatory T (Treg) cells. Although Th1 cells may be more important in allograft rejection by producing inflammatory cytokines capable of driving a cellular immune response such as IFN-γ and interleukin (IL)-2, Th2 cells may also be involved in rejection through the activation of eosinophils and promoting a humoral immune response (via cytokines IL4, 5 and 13) [21, 22]. There is increasing evidence that Th17 cells contribute to allograft rejection although the susceptibility of these cells to immune regulation remains unclear [23]. Although Treg cells are capable of inducing immune tolerance in animal models of transplantation, the role of these cells in humans remains unclear [24, 25]. Both CD4+ and CD8+ T cells can mediate allograft injury either directly or indirectly through the production

death by promoting caspase-induced cell apoptosis by releasing perforin and granzymes A

receptor interaction but they can also cause indirect cell damage by secreting TNF-α and TNFβ, which subsequently bind to TNF-receptors on endothelial or tubular cells resulting in cell

There is increasing evidence that in solid organ transplantation, B cells play an important role in the immune response to an allograft through the production of antibodies (resulting in the development of acute and chronic antibody mediated rejection [AMR]), but these cells may also have an important role in the support of T cells (resulting in the development of acute cellular rejection) [29]. Most peripheral B cells are produced in the bone marrow and contin‐

T cells can directly induce cell apoptosis via Fas-ligand/Fas-

and B intracellularly or via Fas-ligand/Fas-receptor interaction between CD8+

of cytokines or by activating vascular endothelial cells. CD8+

allograft [26]. Similarly, CD4+

apoptosis [27, 28].

*2.2.2. B cells*

rejection [20].

or

349

T cells can directly cause cell

T cells and

#### **2.2. Role of T and B cells in allograft rejection**
