**3. Human Leukocyte Antigen (HLA)**

The HLA system is the name given to the human MHC, which was first described by Jean Dausset in 1952 after observing the development of alloantibodies to leukocytes following blood transfusions [36]. The HLA system comprises a group of cell-surface antigen-presenting proteins encoded by a region on the short arm of chromosome 6 and is divided into class I and class II molecules. Humans have three class I HLA (A, B, C) that are present on all nucleated cells and six class II HLA (DPA1, DPB1, DQA1, DQB1, DRA, DRB1) that are present only on antigen-presenting cells and lymphocytes. Class I HLA presents intracellular antigens while class II HLA present extracellular antigens. HLA are highly polymorphic with almost 6000 HLA Class I and over 1500 HLA Class II alleles having been identified [37]. Three of the seven heterodimers (HLA-A, -B, and -DRB1) contribute to the majority of the immunogenicity of mismatched antigens and therefore traditional HLA-typing methods have primarily focussed on these alleles.

HLA play an important role in the immune system by controlling immune responses through antigen presentation and distinguish "self" from "non-self". Since its introduction after the first International Histocompatibility Workshop (IHWS) in 1964, HLA matching has formed the cornerstone of deceased-donor kidney allocation policies worldwide [38]. By the first World Health Organization nomenclature meeting in 1970, 27 HLA antigens were identified. The discovery of new antigens on occasion splits previously known 'broad' antigens into two or more antigens, termed 'split' antigens. For example, the A9 broad antigen was split to A23 and A24 split antigens, whereas the DR2 broad antigen was split to DR15 and DR16 split antigens [39]. HLA matching criteria may vary with regards to consideration of broad or split 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 for any given donor [41].

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

The HLA system is the name given to the human MHC, which was first described by Jean Dausset in 1952 after observing the development of alloantibodies to leukocytes following blood transfusions [36]. The HLA system comprises a group of cell-surface antigen-presenting proteins encoded by a region on the short arm of chromosome 6 and is divided into class I and class II molecules. Humans have three class I HLA (A, B, C) that are present on all nucleated cells and six class II HLA (DPA1, DPB1, DQA1, DQB1, DRA, DRB1) that are present only on antigen-presenting cells and lymphocytes. Class I HLA presents intracellular antigens while class II HLA present extracellular antigens. HLA are highly polymorphic with almost 6000 HLA Class I and over 1500 HLA Class II alleles having been identified [37]. Three of the seven heterodimers (HLA-A, -B, and -DRB1) contribute to the majority of the immunogenicity of mismatched antigens and therefore traditional HLA-typing methods have primarily focussed

HLA play an important role in the immune system by controlling immune responses through antigen presentation and distinguish "self" from "non-self". Since its introduction after the first International Histocompatibility Workshop (IHWS) in 1964, HLA matching has formed the cornerstone of deceased-donor kidney allocation policies worldwide [38]. By the first World Health Organization nomenclature meeting in 1970, 27 HLA antigens were identified. The discovery of new antigens on occasion splits previously known 'broad' antigens into two or more antigens, termed 'split' antigens. For example, the A9 broad antigen was split to A23 and A24 split antigens, whereas the DR2 broad antigen was split to DR15 and DR16 split antigens [39]. HLA matching criteria may vary with regards to consideration of broad or split

organ transplantation remains unclear.

350 Current Issues and Future Direction in Kidney Transplantation

on these alleles.

**3. Human Leukocyte Antigen (HLA)**

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‐ clusive [42-44].

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

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‐ matches in the modern era.
