Paradoxically, the discovery of diversity in tissue histocompatibility antigens led to the triumphant first successful kidney transplantation between two identical twin brothers . Although initial progress with immunosuppression was somewhat disappointing [2,3], the incompatibility between donors and recipients initiated the development of a crossmatch test preventing hyperacute rejections . Meanwhile, scientists painstakingly unravelled the identity of the histocompatibility leukocyte antigen (HLA) using the sera of mothers who were uniquely immunized to fathers’ HLA antigens [5,6]. The list of HLA antigens grew exponentially with current commercial assays identifying thousands of high-resolution four-digit class I and class II HLAs . While the cytotoxic assay practically eliminated the risk of hyperacute rejection, the flow crossmatch elevated the sensitivity to select candidates without donor-specific antibodies (DSAs) . When improvements in immunosuppression overcame acute rejection, especially by using induction therapy, the impact of HLA diversity between donor and recipient appeared to be under control. However, initial analysis of long-term kidney allograft survival showed clear benefits of HLA matching and inspired a national programme for shipping zero (HLA-A, B, DR) mismatched transplants to compatible recipients across the country [9,10]. Accumulation of sensitized and very highly sensitized patients warranted an additional programme introduced in December 2014, for at least 98% calculated panel reactive antibody (cPRA) patients. The impact of the programme for at least 98% cPRA patients was an overwhelming success with an increase in transplants among very highly sensitized patients . All of this progress was made possible by a breakthrough in technology offering beads individually coated with HLA proteins, as these beads characterized unacceptable HLAs for sensitized patients prior-to-transplantation, and de-novo sensitization with donor HLAs after transplantation . The current long-term kidney allograft survival for patients transplanted in 2010 is 9.9 years for deceased donors and 14.2 years for live donors . At the same time, zero HLA mismatched recipients in the best quality donor/recipient pairs displayed an average survival of 24.2 years [14,15], manifesting the often hidden possibilities in HLA matchings. Similarly, the 25-year old Acceptable Mismatch programme revealed the success of identifying ‘permissive’ HLA antigens for offering kidney transplants to very highly sensitized patients .
The major still unresolved challenge remains whether the usage of two-digit HLA is sufficient or rather a four-digit HLA needs to be required in organ transplantation. While usually two-digit HLAs are reported for donors and recipients, the real progress in the last decade has been achieved using four-digit HLAs: single antigen beads provide data on antibody profiles utilizing four-digit HLAs; the HLAMatchmaker epitope analysis for antibody binding and immunogenicity also requires four-digit HLAs; and, the Kosmoliaptsis algorithm analysis for the quantification of immunogenicity is also based on the physiochemical properties of four-digit HLAs. Because large national databases register two-digit HLAs, the most advanced analyses in recent years utilized the conversion from two to four digits [17–21]. This duality of two-digit reality vs. four-digit advanced analysis needs to be changed by uniform national policy requiring four-digit HLA for all loci to fully benefit from the most advanced scientific achievements. The available technology may unleash the power of the clinical possibilities revealed by these reviews: all of them utilize four-digit HLA databases mostly converted to make their conclusions based on retrospective analyses. The ‘real’ four-digit HLAs are necessary for prospective future decision-making prior and after transplantation.
It is now obvious that the revolution in HLA identification is happening. Multiauthor editorial by leading experts in transplantation declared ‘it is well accepted that HLA antibodies specifically recognize a wide range of epitopes present on HLA antigens and that molecularly defined high resolution alleles corresponding to the same low resolution antigen can possess different epitope repertoire’ . They conclude that allelic HLA compatibility is more accurate for sensitized patients. The Sensitization in Transplantation Assessment of Risk (STAR) group of clinical experts provided additional recommendations on HLA testing and assessment of memory and primary immune responses . They write the following ‘Given the complexity of HLA genetics and its polymorphism in different ethnic groups, imputation of missing HLA data may introduce substantial bias’. There are already convincing evidence about the impact of all loci and how high resolution transforms clinical realities [24,25]. The Canadian group evaluated ‘missing’ DQA, DPA and DPB in the cPRA concluding that many sensitized patients had these antibodies elevating their cPRA values in 20% of patients . The Australians type donors at four-digit level for HLA-A, HLA-B, HLA-Cw, HLA-DRB1 and HLA-DQB1 to maximize chances of getting a donor for sensitized patients . Furthermore, in the national kidney paired program (KPD), the Australians fully type donors for HLA-A, HLA-B, Cw, DRB1, DPB1, DQB1, DQA1, DRB3, DRB4 and DRB5 at high resolution . The same multiple antigens are required in the national programme in Canada, but four-digit resolution is done by some laboratories or when needed to protect sensitized patients . In the United States, the required antigens for donors are HLA A, B, Bw4, Bw6, C, DR, DR51, DR52, DR53, DQA1, DQB1 and DPB1 at the level of serological splits and for candidates are HLA A, B, Bw4, Bw6 and DR. CPRA is calculated without DQA1, DPB1 and DPA1 antigens . Without a doubt, a ‘no return’ critical point has been crossed and further progress requires the four-digit HLA identification of all loci in organ transplantation.
The current issue of the Current Opinion in Transplantation reviews the most innovative thinking from Europe and North America about the insightful approach to HLA. The importance of DQB/DQA alloantigens for kidney allograft rejection is presented by Dr Anat Tambur (pp. 470–476), who for the last 10 years has focused on the complexity of DQB/DQA immunogenicity . The DSA directed to DQB/DQA bind to epitopes either on DQB or DQA chain as well as to epitopes formed by two chains . The current review describes the aspects of differences between DR and DQ antigens in the levels of distribution and polymorphism as well as their multiple functional abilities. The author suggests that DQ antigens display an increased immunogenicity compared with DR antigens and that the mechanism of such immunogenicity warrants further explanation.
A conceptually revolutionary definition of immunogenicity is described by Dr Kosmoliaptsis’ group with molecular level analysis of physiochemical properties of individualized donor/recipient pairs (pp. 477–485). His group lined up amino acids of polymorphic HLA regions calculating their hydrophobic (HMS), electrostatic (EMS) and amino acid (AMS) mismatch scores as a precise quantitative measure of potential immunogenicity [19,30]. The authors discuss how HMS, EMS or AMS numbers, expressed in a continuous immunogenicity scale, correlate with different clinical events. This approach may completely change the quantification of probabilities in positive and negative events facing each allogeneic transplant. The flexibility of HMS, EMS and AMS scales allows for their adjustment based on variables such as age, race, sex and multiple other factors important for an individual patient and her/his unique transplant. As it is called by its inventor, the Cambridge HLA immunogenicity algorithm may be a means for precision medicine in transplantation.
There are two other aspects of HLAs, which are addressed in the reviews, namely more advanced methods to evaluate antibody response to HLA alloantigens and HLA immunogenicity. For the last 30 years, Dr René Duquesnoy has performed pioneering work by preparing an inventory of epitopes (eplets) . His visionary theoretical concept of hundreds polymorphic sites on HLA alloantigens need to be painstakingly verified . Using a truly Benedictine precentor's patience, Rene organized a now well recognized inventory of verified eplets (www.epregistry.com.br). In this issue, he presents his personal view (pp. 486–492) of further developments wherein the concept of epitopes expanded into self/nonself-combinations . The practical aspects of epitopes have been documented in the concept of acceptable mismatches in details presented in this issue by Dr Heidt and colleagues (pp. 493–499). This programme succeeded for the last 25 years by Eurotransplant facilitated transplantation of kidneys in a large number of very highly sensitized patients. The concept enlists HLA alloantigens and epitopes which are weakly or nonimmunogenic as self, thereby significantly increasing chances for finding a well tolerated donor for highly sensitized candidates . In this issue, the authors explained their vision and their work to expand the acceptable epitopes as the future of a computerized search. The same way of thinking is further presented by a Canadian group Drs. Wiebe and Nickerson (pp. 500–505), who in practical terms document a usefulness of epitopes to match donor/recipient pairs . Their concept of matching using epitopes and immunogenicity scores may become a computerized powerhouse for the precision medicine in organ transplantation . They stress that those new methods of HLA molecular mismatch assess the alloimmune risk factors, at both pre and posttransplant levels to help evaluating in the clinical context kidney, lung and pancreas transplants. Consistent accumulation of knowledge should facilitate decision making about the conditions for allowing safe transplantation in high-risk patients and minimizing immunosuppression in stable or infected patients.
The HLA molecules are the strongest polymorphic antigenic stimulators of allografts. The host's immune response distinguishes intricate differences of donor polymorphic amino acids and the quantification of this response may be predicted by the precise measurement of immunogenicity. Indeed, class I and class II have different molecules and their expression is distinct on different cells. The quantification of antibody and cellular responses may be reflected by the immunogenicity of different HLAs. Each of the current reviews provides an addition to the emerging ‘precision medicine’, namely by correlating the molecular HLA level with clinical events. The next level of analysis should be considered with computational 3D HLA structures of clinically important immunogenic epitopes.
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1. Merrill JP, Murray JE, Harrison JH, Guild WR. Successful homotransplantation of the human kidney between identical twins. J Am Med Assoc 1956; 160:277–282.
2. Chan GL, Canafax DM, Johnson CA. The therapeutic use of azathioprine in renal transplantation. Pharmacotherapy 1987; 7:165–177.
3. Zukoski CF. Experimental suppression of allograft rejection: background and application. J Lancet 1968; 88:159–161.
4. Patel R, Terasaki PI. Significance of the positive crossmatch test in kidney transplantation. N Engl J Med 1969; 280:735–739.
5. Duquesnoy RJ, Honger G, Hosli I, et al. Detection of newly antibody-defined epitopes on HLA class I alleles reacting with antibodies induced during pregnancy. Int J Immunogenet 2016; 43:200–208.
6. Duquesnoy RJ, Honger G, Hosli I, et al. Identification of epitopes on HLA-DRB alleles reacting with antibodies in sera from women sensitized during pregnancy. Hum Immunol 2016; 77:214–222.
8. Gebel HM, Lebeck LK. Crossmatch procedures used in organ transplantation. ClinLab Med 1991; 11:603–620.
9. Terasaki PI, Gjertson DW, Cecka JM, Takemoto S. HLA matching for improved cadaver kidney allocation. Curr Opin Nephrol Hypertens 1994; 3:585–588.
10. Stegall MD, Dean PG, McBride MA, Wynn JJ. Survival of mandatorily shared cadaveric kidneys and their paybacks in the zero mismatch era. Transplantation 2002; 74:670–675.
11. Hart A, Gustafson SK, Skeans MA, et al. OPTN/SRTR 2015 Annual Data Report: early effects of the new kidney allocation system. Am J Transplant 2017; 17 (Suppl 1):543–564.
12. Tait BD. Detection of HLA antibodies in organ transplant recipients: triumphs and challenges of the solid phase bead assay. Front Immunol 2016; 7:570.
13. Matas AJ, Smith JM, Skeans MA, et al. OPTN/SRTR 2012 Annual Data Report: kidney. Am J Transplant 2014; 14 (Suppl 1):11–44.
14. Takemoto S, Terasaki PI, Cecka JM, et al. Survival of nationally shared, HLA-matched kidney transplants from cadaveric donors. The UNOS Scientific Renal Transplant Registry. N Engl J Med 1992; 327:834–839.
15. Takemoto SK, Terasaki PI, Gjertson DW, Cecka JM. Twelve years’ experience with national sharing of HLA-matched cadaveric kidneys for transplantation. N Engl J Med 2000; 343:1078–1084.
16. Heidt S, Haasnoot GW, van Rood JJ, et al. Kidney allocation based on proven acceptable antigens results in superior graft survival in highly sensitized patients. Kidney Int 2018; 93:491–500.
17. Duquesnoy RJ, Awadalla Y, Lomago J, et al. Retransplant candidates have donor-specific antibodies that react with structurally defined HLA-DR,DQ,DP epitopes. Transpl Immunol 2008; 18:352–360.
18. Kosmoliaptsis V, Bradley JA, Sharples LD, et al. Predicting the immunogenicity of human leukocyte antigen class I alloantigens using structural epitope analysis determined by HLAMatchmaker. Transplantation 2008; 85:1817–1825.
19. Kosmoliaptsis V, Sharples LD, Chaudhry AN, et al. Predicting HLA class II alloantigen immunogenicity from the number and physiochemical properties of amino acid polymorphisms. Transplantation 2011; 91:183–190.
20. Wiebe C, Pochinco D, Blydt-Hansen TD, et al. Class II HLA epitope matching-A strategy to minimize de novo donor-specific antibody development and improve outcomes. Am J Transplant 2013; 13:3114–3122.
21. Wiebe C, Nevins TE, Robiner WN, et al. The synergistic effect of class II HLA epitope-mismatch and nonadherence on acute rejection and graft survival. Am J Transplant 2015; 15:2197–2202.
22. Duquesnoy RJ, Gebel HM, Woodle ES, et al. High-resolution HLA typing for sensitized patients: advances in medicine and science require us to challenge existing paradigms. Am J Transplant 2015; 15:2780–2781.
23. Tambur AR, Campbell P, Claas FH, et al. Sensitization in Transplantation: Assessment of Risk (STAR) 2017 Working Group Meeting Report. Am J Transplant 2018; [Epub ahead of print].
24. Ferrari P, Cantwell L, Ta J, et al. Providing better-matched donors for HLA mismatched compatible pairs through kidney paired donation. Transplantation 2017; 101:642–648.
25. Tinckam KJ, Liwski R, Pochinco D, et al. cPRA increases with DQA, DPA, and DPB unacceptable antigens in the Canadian cPRA calculator. Am J Transplant 2015; 15:3194–3201.
26. Ferrari P, Fidler S, Wright J, et al. Virtual crossmatch approach to maximize matching in paired kidney donation. Am J Transplant 2011; 11:272–278.
28. Tambur AR. HLA-DQ antibodies: are they real? Are they relevant? Why so many? Curr Opin Organ Transplant 2016; 21:441–446.
29. Tambur AR. Auto- and allo-epitopes in DQ alloreactive antibodies. Curr Opin Organ Transplant 2016; 21:355–361.
30. Kosmoliaptsis V, Chaudhry AN, Sharples LD, et al. Predicting HLA class I alloantigen immunogenicity from the number and physiochemical properties of amino acid polymorphisms. Transplantation 2009; 88:791–798.
31. Duquesnoy RJ, Marrari M, da M Sousa LC, et al. 16th IHIW: a website for antibody-defined HLA epitope registry. Int J Immunogenet 2013; 40:54–59.
32. Duquesnoy RJ. Human leukocyte antigen epitope antigenicity and immunogenicity. Curr Opin Organ Transplant 2014; 19:428–435.
33. Wiebe C, Nickerson P. Strategic use of epitope matching to improve outcomes. Transplantation 2016; 100:2048–2052.
34. Wiebe C, Ho J, Gibson IW, et al. Carpe diem-Time to transition from empiric to precision medicine in kidney transplantation. Am J Transplant 2018; [Epub ahead of print].