**9. Acceptable HLA-mismatch programs**

accessibility, recognition, and subsequent reactivity [94]. Almost 200 class I and II epitopes have been defined by Luminex technology [95]. Some epitopes are shared across different HLA alleles while some are unique to single or more restricted numbers of HLA alleles. While there are considerable differences in HLA antigen frequencies between different ethnic groups,

**Figure 5.** Impact of HLA-A, -B triplet (T) matching on 5-year graft survival rates in zero-HLA-DR-mismatched kidney transplants in a cohort of United Nation of Organ Sharing (UNOS) renal transplant recipients between 1987 and 1999

The concept of acceptable HLA-mismatch identifies mismatched HLA-antigens that could be considered as compatible at a structural or functional level. It is based on the principle that each HLA antigen is structurally unique and that an individual cannot mount an immuno‐ logical response against an epitope expressed by their own HLA, i.e. one cannot react against shared 'self' epitopes [105, 106]. It has been demonstrated that such acceptable HLA-mis‐ matches would result in a negative CDC cross-match and therefore allow transplantation to

Acceptable HLA-mismatches can be identified using HLAMatchmaker or the Luminex platform. HLAMatchmaker is a computer algorithm that regards each HLA antigen as a string of polymorphic amino acid configurations in antibody-accessible positions (epitopes) formed by triplets or eplets [99, 100]. For any given set of HLA antigens, HLAMatchmaker can define the number of triplet or eplet mismatches present against any foreign HLA antigen and hence define the HLA antigens that are mismatched at the broad antigen level but matched at the eplet level, i.e. acceptable HLA-mismatches. Graft outcomes of HLAMatchmaker-identified 0-2 triplet-mismatched kidney transplant recipients are similar compared to recipients with 0

HLA-mismatch at the HLA-A, -B and –DR loci (Figure 5) [101]

HLA – human leukocyte antigen, UNOS – United Nation Organ Sharing, T - triplets.

CREGs are more evenly distributed [96].

(adapted from *Duquesnoy et al* Transplantation 2003) [101].

360 Current Issues and Future Direction in Kidney Transplantation

safely proceed [97, 98].

Successful acceptable HLA-mismatch programs have been implemented in many countries, including Europe, United Kingdom and United States [45, 114-116]. Eurotransplant Acceptable Mismatch Program was established in mid 1970 to improve the transplant potential of highly sensitized transplant candidates. Over the ensuing decade, eleven other similar programs were introduced throughout Europe [103]. Although there is considerable variation in PRA cut-off to define highly sensitized transplant candidates, it is generally accepted that PRA >80% may be the most appropriate cut-off. Table 2 highlights the results of the established acceptable mismatch programs.


PRA – panel reactive antibody, HLA – human leukocyte antigen

**Table 2.** Description of allocation schemes based on acceptable HLA-mismatch.

The Eurotransplant Acceptable Mismatch Program is the largest and most successful program and runs in parallel with the Eurotransplant Kidney Allocation System (ETKAS) to identify acceptable HLA-mismatches in potential highly sensitized transplant candidates through comprehensive serum screening for acceptable mismatches. The introduction of the acceptable mismatch program has significantly reduced waiting time for highly sensitized transplant candidates whilst achieving comparable short and long-term graft outcomes to unsensitized transplant recipients [100].

**References**

[1] Fearon D, Locksley R. The instructive role of innate immunity in the acquired im‐

The Evolution of HLA-Matching in Kidney Transplantation

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

363

[2] Banchereau J, Briere F, Caux C, et al. Immunobiology of dendritic cells. Ann Rev Im‐

[3] Banchereau J, Steinman RM. Dendritic cells and the control of immunity. Nature

[4] Coates PTH, Thomson AW. Dendritic cells, tolerance induction and transplant out‐

[5] Morelli A, Thomson A. Dendritic cells: regulators of alloimmunity and opportunities

[6] Gallucci S, Lolkema M, Matzinger P. Natural adjuvants: endogenous activators of

[7] Gallucci S, Matzinger P. Danger signals: SOS to the immune system. Curr Opin Im‐

[8] Morelli A, Zahorchak A, Larregina A, et al. Regulation of cytokine production by mouse myeloid dendritic cells in relation to differentiation and terminal maturation

[9] Rescigno M, Martino M, Sutherland C, Gold M, Ricciardi-Castagnoli P. Dendritic cell survival and maturation are regulated by different signaling pathways. J Exp Med

[10] Nankivell B, Alexander S. Rejection of the kidney allograft. N Engl J Med 2010; 363

[11] Hagerty D, Allen P. Processing and presentation of self and foreign antigens by the

[12] Kreisel D, Krupnick A, Balsara K, et al. Mouse vascular endothelium activates CD8+ T lymphocytes in a B7-dependent fashion. J Immunol 2002; 169 (11): 6154.

[13] Larsen C, Morris P, Austyn J. Migration of dendritic leukocytes from cardiac allog‐ rafts into host spleens. A novel pathway for initiation of rejection. J Exp Med 1990;

[14] Suciu-Foca N, Colovai A, Ciubotariu R, Cortesini R. Mapping of HLA-DR determi‐

[15] Benichou G, Valujskikh A, Heeger PS. Contributions of direct and indirect T cell al‐

loreactivity during allograft rejection in mice. J Immunol 1999; 162: 352.

mune response. Science 1996; 272 (5258): 50.

come. Am J Transplant 2002; 2 (3): 299.

dendritic cells. Nat Med 1999; 5: 1249.

for tolerance induction. Immunol Rev 2003; 196: 125.

induced by LPS or CD40 ligation. Blood 2001; 98 (5): 1512.

renal proximal tubule. J Immunol 1992; 148: 2324.

nants recognized via the indirect pathway. Graft 1999; 2: 28.

munol 2000; 18: 767.

munol 2001; 13: 114.

1998; 188: 2175.

(15): 1451.

171: 307.

1998; 392: 245.

The deceased donor kidney allocation algorithm in Australia does not consider acceptable HLA-mismatches for highly sensitized transplant candidates. We are currently investigating the impact of identifying and incorporating acceptable mismatches into the deceased-donor kidney allocation model and our preliminary data suggest that an acceptable mismatch program could result in an improvement in transplant potential of 1 in 10 highly sensitized renal transplant recipients (PRA >80%) with a potential reduction in average transplant waitlist time of 33 months [104].
