**5. Cross-matching techniques**

MICA and MICB genes are polymorphic but not as much as the classical HLA class I genes. Over 70 MICA alleles and over 30 MICB alleles have been described [23]. Unlike HLA class I where the polymorphic residues are located mainly in the region that forms the peptide binding groove, polymorphism in MIC is more dispersed throughout the α2 and α3 domains. There is also polymorphism in the trans-membrane region. Many MIC antigens have the same extracellular domains with the only differences lying in the

MICA and MICB antigens are constitutively expressed on epithelial cells, especially those of the gastrointestinal tract and on fibroblasts, monocytes, dendritic cells and on endothelial cells. They are not constitutively expressed on lymphocytes. They are however up regulated in

The structure of MICA is similar to that of HLA class I but has some striking differen‐ ces. Like HLA class I, MICA has three extracellular domains (α1, 2 and 3), a transmem‐ brane region and a cytoplasmic domain. Unlike HLA class I, the MICA protein does not associate with β2 microglobulin. The MICA α1 and 2 domains form a platform that is analogous to the platform formed by HLA class I α1 and 2 domains. In HLA class I, this platform forms the peptide binding groove. The MICA molecule however has extensive disordering of sections of the alpha helix in the α2 domain resulting in a very shallow groove, incapable of binding peptide. The MICA α1 and 2 platform domains do not in‐ teract with the α3 domain except for being linked together through a short linker chain.

The NKG2D receptor forms a complex with MICA by binding orthogonal to the alpha helices

HLA presents the major genetic barrier to stem cell transplantation. However, evidence that other genetic systems are involved includes GvHD and some degree of rejection even when transplanting with HLA identical siblings. A non HLA system which is thought to contribute to this is the minor histocompatibility antigen (mHA) system. Mi‐ nor histocompatibility antigens comprise of peptides derived from proteins in which some degree of polymorphism exists such there may be differences between the patient and donor repertoires. These peptides can be presented to the immune system by both

The best characterised minor antigens are the Y chromosome derived HY peptide and the autosomal HA1 to HA5 peptides. Minor histocompatibility antigens such as HA1 and HA2 have restricted tissue distribution and are present normally only on haematopoietic cells. Others such as HY are more ubiquitously distributed, expressed for instance on gut epithelium. HA1 and HA2 are expressed on leukaemic cells and some tumour cells, making them potential targets for cellular therapy. Minor HLA antigens are restricted by certain HLA types such as

trans-membrane regions.

380 Current Issues and Future Direction in Kidney Transplantation

This allows for some flexibility in the structure.

of the platform α1 and 2 domains.

HLA class I and II antigens.

HLA-A2 for instance.

**4.3. Minor histocompatibility antigens**

stressed cells.

Crossmatching was developed in an attempt to identify recipients who are likely to de‐ velop acute vascular rejection of a graft from a given donor. This phenomenon, hyper‐ acute rejection (HAR) [24], is a result of preformed antibodies against the donor; referred to as donor-specific antibodies (DSA). Such antibodies are usually formed as the result of previous exposure to HLA, generally through pregnancy, blood transfusion or previous transplantation [25]. There are other debated forms of developing anti-HLA Abs such as via microbial exposure but the above three are thought to be the most prevalent. Particu‐ larly relevant is the exposure of women during pregnancy, to their partner's HLA. This commonly results in direct sensitization against the partner, potentially making him an unsuitable living donor. HAR may also occur in blood group incompatible transplanta‐ tion or rarely as a result of other non-HLA antibodies.

Preformed antibodies cause rejection by binding to HLA antigens expressed on the endothe‐ lium of vessels in the transplanted kidney, resulting in activation of the complement cascade with resultant thrombosis and infarction of the graft. HAR can occur immediately upon reperfusion of the donor kidney. This catastrophic outcome necessitates the immediate removal of the graft. Clearly avoiding HAR is desirable and crossmatching helps predict and hence prevent this [17].

There are different types of crossmatch tests available.
