Differences in Immunogenicity of HLA Antigens and the Impact of Cross-Reactivity on the Humoral Response

Abstract

BackgroundInformation about differences in immunogenicity of various HLA antigens may help guide donor selection and identify mismatches to avoid for patients likely to need retransplantation. To date, antibody responses to a wide array of individual mismatched antigens have not been evaluated.MethodsFrequencies of antibodies to mismatched HLA-A, HLA-B, HLA-DR, and HLA-DQ antigens were determined for 703 renal transplant patients who had no detectable donor-specific antibody before transplantation. The impact of cross-reactive group matching and production of antibodies cross-reactive with mismatched antigens were also assessed. Antibodies were identified using multiplexed bead assays.ResultsThe overall mean frequencies were similar for HLA-A (53.2%), HLA-DR (52.6%), and HLA-DQ (59.0%) antibodies, but significantly lower for HLA-B antibodies (42.4%). However, the response to individual antigens ranged from 15.0% to 76.2%. Antibody frequencies were reduced significantly for 54 of 62 specificities when the patient possessed an antigen cross-reactive with the donor mismatch, but the magnitude of the effect was variable and ranged from 8% to 83%. Moreover, there was directionality in the protective effect of cross-reactive group matching. Overall mean donor-specific antibody frequencies were comparable for men and women except for a significantly higher frequency of antibodies to HLA-DR among men (56.6% vs. 47.8%, P=0.004). Overall mean frequencies in blacks were higher than, or comparable to those of, whites, but differences were not significant.ConclusionThere is considerable variability in the immunogenicity of different HLA antigens that is impacted by the presence or absence of cross-reactive antigens in the patient’s phenotype. This information can be used to augment the immunologic evaluation of donor-recipient pairs.

HLA-DQ Mismatches and Rejection in Kidney Transplant Recipients

“…There is also considerable variability in the immunogenicity of individual HLA, and matching at the epitope level may improve our understanding of otherwise unexplained sensitization status induced by a given HLA mismatch (17). Although HLA-DQ and -DR may be closely related at an antigen level, it has been shown that small differences in one or more epitopes between donors and recipients at either locus are sufficient to generate a humoral and/or T cell-mediated immune response (18,19).…”

The mechanism of humoral immune response to allogeneic organ transplantation

“…При этом одной из главных причин, негативно влияющих на продолжительность жизни трансплантата, является выработка антител к не-совпадающим HLA-антигенам, причем даже еди-ничное несовпадение может приводить к развитию сенсибилизации [62]. Подбор оптимально совмес-тимой пары «донор-реципиент» на основе оценки «эпитопной нагрузки» представляется одним из наиболее эффективных и перспективных направ-лений в преодолении тканевой несовместимости в аллогенной трансплантации.…”

“…3 данные имеют боль-шую практическую ценность, так как позволяют оценить и спрогнозировать риск гуморального от-торжения при наличии определенных несовпадений в HLA-фенотипе донора и реципиента. В указанной публикации также можно обнаружить данные, ха-рактеризующие иммуногенность антигенов ло-кусов В, DR и DQ [62]. Кроме того, установлены некоторые общие закономерности выработки HLA-антител к антигенам различных локусов.…”

Investigation of Human Leucocyte Antigen Epitopes in Organ Transplantation: Review

“…5,7,8 Böbrek naklinde, HLA tam uyumlu donörden yapılan nakiller ile düşük HLA uyumu olan donör-lerden yapılan nakillerin greft sağkalımı oranlarının benzer olması, araştırmacıları HLA epitoplarının antikor ile etkileştiği bölgelere yoğunlaştırmıştır. 9 Bu kapsamda 2000'li yılların başında Duquesnoy tarafından HLA "matchmaker" programı kullanılmaya başlanmıştır.…”

“…Yamalardan her ikisi de en az bir adet nonself rezidü içerebilir ya da yamalardan biri, bir ya da daha fazla nonself rezidüye sahip iken diğeri self rezidü-lere sahip olabilir. 7,9 Humoral mekanizmalar tam olarak anlaşılmamasına rağmen, her bireyin kendi hücreleri üzerinde eksprese olan reseptörlerin epitopları için düşük aviditeli B hücre repertuvarına sahip olduğu bilinmektedir. Bu epitoplar, B hücre-lerinin aktivasyonuna ve antikor üretimine sebep olmaz.…”