*2.2.1. T cells*

The most common form of acute rejection of allogeneic tissues and allografts involve the activation of recipient's T cells (i.e. adaptive immune response) directed against donor MHC antigens or MHC-derived peptides presented by either the donor's or recipient's APC [5]. DC are considered the most potent form of APC in humans through their capacity for antigen uptake and processing of foreign antigens into peptides which can then be presented to antigen-specific T cells via MHC complexes, leading to activation and clonal expansion of naïve and memory T cells (i.e. primary and secondary immune responses) [2]. During steady state, DC reside as functionally immature cells in most tissues. Following organ transplantation, the systemic effects of donor brain death and/or ischaemia-reperfusion injury are sufficient to generate an inflammatory response to mature these DC during their migration carrying donor antigens from the transplanted organ to the recipient's secondary lymphoid organs including the draining lymph nodes and spleen [6, 7]. DC may also be activated via CD40-CD40L interaction, with activated cells (e.g. platelets, T cells, mast cells) within transplanted allografts the potential source of CD40L. This interaction may regulate DC migration possibly via tumour necrosis factor (TNF)-α production by DC [8]. DC maturation and immunostimulatory capacity are dependent on nuclear factor kappa B (NF-κB)-dependent gene transcription including genes involved in the expression of adhesion molecules, chemotactic factors and the production of various cytokines [9]. Although DC are very efficient in presenting donor antigens to T cells, other cell types including tubular epithelial cells, endothelial cells, macro‐ phages and also B cells can participate in T cell interaction, the latter by capturing and presenting foreign antigens via their surface immunoglobulins and MHC class II molecules [10-12].

Direct and indirect allorecognition of allogeneic antigens are mediated by donor-derived and recipient's DC respectively. Donor DC present donor peptide mounted on donor MHC molecules to recipient's T cells following migration of donor DC to T cell areas of lymphoid tissues ('passenger leukocytes') in response to surgery [13]. This mode of presentation is termed *direct allorecognition* and is particularly important in the initiation of acute rejection resulting from a powerful alloantigen-specific T cell response directed against allogeneic antigens [14]. The finding of >90% of infiltrating recipient's T cells involved in recognising donor-derived MHC molecule directly presented by donor DC during acute rejection of allogeneic skin graft in mice support the existence of this direct pathway [15]. Furthermore, the frequency of direct donor-specific hyporeactivity is similar between long-term renal transplant recipients with good graft function compared to those recipients with established chronic rejection suggesting that direct allorecognition is not the predominant response in 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+ or 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 rejection [20].

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 of cytokines or by activating vascular endothelial cells. CD8+ T cells can directly cause cell death by promoting caspase-induced cell apoptosis by releasing perforin and granzymes A and B intracellularly or via Fas-ligand/Fas-receptor interaction between CD8+ T cells and allograft [26]. Similarly, CD4+ T cells can directly induce cell apoptosis via Fas-ligand/Fasreceptor 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 apoptosis [27, 28].

### *2.2.2. B cells*

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

The most common form of acute rejection of allogeneic tissues and allografts involve the activation of recipient's T cells (i.e. adaptive immune response) directed against donor MHC antigens or MHC-derived peptides presented by either the donor's or recipient's APC [5]. DC are considered the most potent form of APC in humans through their capacity for antigen uptake and processing of foreign antigens into peptides which can then be presented to antigen-specific T cells via MHC complexes, leading to activation and clonal expansion of naïve and memory T cells (i.e. primary and secondary immune responses) [2]. During steady state, DC reside as functionally immature cells in most tissues. Following organ transplantation, the systemic effects of donor brain death and/or ischaemia-reperfusion injury are sufficient to generate an inflammatory response to mature these DC during their migration carrying donor antigens from the transplanted organ to the recipient's secondary lymphoid organs including the draining lymph nodes and spleen [6, 7]. DC may also be activated via CD40-CD40L interaction, with activated cells (e.g. platelets, T cells, mast cells) within transplanted allografts the potential source of CD40L. This interaction may regulate DC migration possibly via tumour necrosis factor (TNF)-α production by DC [8]. DC maturation and immunostimulatory capacity are dependent on nuclear factor kappa B (NF-κB)-dependent gene transcription including genes involved in the expression of adhesion molecules, chemotactic factors and the production of various cytokines [9]. Although DC are very efficient in presenting donor antigens to T cells, other cell types including tubular epithelial cells, endothelial cells, macro‐ phages and also B cells can participate in T cell interaction, the latter by capturing and presenting foreign antigens via their surface immunoglobulins and MHC class II molecules

Direct and indirect allorecognition of allogeneic antigens are mediated by donor-derived and recipient's DC respectively. Donor DC present donor peptide mounted on donor MHC molecules to recipient's T cells following migration of donor DC to T cell areas of lymphoid tissues ('passenger leukocytes') in response to surgery [13]. This mode of presentation is termed *direct allorecognition* and is particularly important in the initiation of acute rejection resulting from a powerful alloantigen-specific T cell response directed against allogeneic antigens [14]. The finding of >90% of infiltrating recipient's T cells involved in recognising donor-derived MHC molecule directly presented by donor DC during acute rejection of allogeneic skin graft in mice support the existence of this direct pathway [15]. Furthermore, the frequency of direct donor-specific hyporeactivity is similar between long-term renal transplant recipients with good graft function compared to those recipients with established chronic rejection suggesting that direct allorecognition is not the predominant response in

of transplant tolerance.

*2.2.1. T cells*

[10-12].

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

348 Current Issues and Future Direction in Kidney Transplantation

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‐ uously circulate as immature cells through secondary lymphoid organs until they encounter antigen. Once activated, B cells become efficient APC by capturing antigen via B-cell receptor, then interacts with naïve T cells through the presentation of antigen by MHC class II molecules to T-cell receptor respectively. Through this interaction coupled with the ability to produce cytokines such as IL-2, B cells are critical for optimal T cell activation and development of T cell memory [30, 31]. Activated B cells may also differentiate into memory B cells or plasma cells, a small proportion of the latter cell type may persist as long-lived plasma cells that reside in the bone marrow ± allografts indefinitely, continuously producing IgG antibodies [32]. APCs such as DC, monocytes and macrophages produce BAFF (B-cell-activating factor belonging to the tumour necrosis factor family), a cytokine which enhances B cell survival [33]. Antibodies produced by terminally differentiated B cells, especially directed against donor antigens, are critical mediators of AMR and associated graft damage through complement activation and Fc-receptor cross-linking, the latter resulting in proinflammatory cytokine release, DC maturation, macrophage phagocytosis and NK cell-mediated antibody-dependent cellular cytotoxicity [34]. Like Treg cells, there is a recently described subset of B cells in humans and mouse known as regulatory B cells, which are capable inhibiting T cell responses, possibly through the production of IL-10 [35]. The clinical significance of these regulatory B cells in organ transplantation remains unclear.

antigens. Split antigen matching appears to be more common and clinically important for HLA-A and-B antigens than for HLA-DR antigens [40]. Not surprisingly, utilization of matching for broad antigens increases the probability of identifying HLA-matched recipients

The Evolution of HLA-Matching in Kidney Transplantation

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

351

Although 0 HLA-mismatched grafts have been shown to have superior graft outcomes compared with grafts with ≥1 HLA-mismatch, a proportion of 0 HLA-mismatched grafts may be complicated by acute rejection, possibly reflecting potential allorecognition of incompati‐ bilities at other minor HLA loci. On the contrary, many HLA-mismatched grafts have excellent graft outcomes without acute rejection, suggesting that under specific circumstances, certain HLA mismatches may be permissible, such as the lack of immunologic response against noninherited maternal HLA antigens (NIMA) as a result of prenatal tolerance development. However, verification of this association between NIMA and graft outcomes remains incon‐

HLA compatibility has also been defined by mismatch acceptability known as acceptable HLAmismatch. These are mismatched HLA antigens that do not result in a positive complement dependent cytotoxicity (CDC) crossmatch [42]. Identification of acceptable HLA-mismatches has been utilised to improve the transplant potential of highly sensitized patients, and this

In most countries worldwide including Australia, the number of HLA-mismatches is calcu‐ lated by the sum of the total number of HLA-mismatches between donor-recipient at HLA-A, B, and DR loci. Large single centre and registry studies have consistently demonstrated an inverse association between increasing number of mismatches and graft and/or patient survival [43-45]. However, with the evolution from serological to molecular-based HLAtyping over time resulting in improved immunological risk stratification of transplant candidates, coupled with the availability of more potent immunosuppression and donor selection has created uncertainty regarding the ongoing clinical importance of HLA-mis‐

Large registry reports including analysis from the Collaborative Transplant Study (CTS) and more recently from the Australia and New Zealand Dialysis and Transplant (ANZDATA) registry have consistently demonstrated a strong association between HLA-matching at the HLA-A, B and DR loci and graft and patient outcomes, independent of donor type, initial

The advantage of improved HLA-matching in reducing acute rejection risk has been demon‐ strated predominantly in renal transplant recipients receiving cyclosporine-based immuno‐ suppressive regimen [49, 50]. Recent retrospective single centre study of live and deceased donor renal transplants has demonstrated that HLA-mismatches remained an important determinant of acute rejection risk in renal transplant recipients receiving quadruple immu‐

concept and application will be discussed in greater details later in this chapter.

**4. Effect of HLA-mismatches and renal transplant outcomes**

immunosuppression, transplant era and even the presence of DSA [46-48].

for any given donor [41].

clusive [42-44].

matches in the modern era.
