Ilias Doxiadis

Publications (182) View all

• Article: 16(th) IHIW: Anti-HLA alloantibodies of the of IgA isotype in re-transplant candidates.

  M-L Arnold, F M Heinemann, P Horn, M Ziemann, N Lachmann, A Mühlbacher, A Dick, A Ender, D Thammanichanond, G F Fischer, S Schaub, M Hallensleben, J Mytilineos, W E Hitzler, C Seidl, I I N Doxiadis, B M Spriewald
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  ABSTRACT: In this multicentre study, sera from 803 retransplant candidates, including 775 kidney transplant recipients, were analysed with regard to the presence and specificity of anti-HLA alloantibodies of the IgA isotype using a modified microsphere-based platform. Of the kidney recipients, nearly one-third (n = 237, 31%) had IgA alloantibodies. Mostly, these antibodies were found in sera that also harboured IgG alloantibodies that could be found in a total of 572 (74%) of patients. Interestingly, IgA anti-HLA antibodies were preferentially targeting HLA class I antigens in contrast to those of the IgG isotype, which targeted mostly both HLA class I and II antigens. Donor specificity of the IgA alloantibodies could be established for over half of the 237 patients with IgA alloantibodies (n = 124, 52%). A further 58 patients had specificities against HLA-C or HLA-DP, for which no information regarding donor typing was available. In summary, these data showed in a large cohort of retransplant candidates that IgA alloantibodies occur in about one-third of patients, about half of these antibodies being donor specific.
  International Journal of Immunogenetics 12/2012; · 1.29 Impact Factor
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  Article: TCR cross-reactivity and allorecognition: new insights into the immunogenetics of allorecognition.

  L J D'Orsogna, D L Roelen, I I N Doxiadis, F H J Claas
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  ABSTRACT: Alloreactive T cells are core mediators of graft rejection and are a potent barrier to transplantation tolerance. It was previously unclear how T cells educated in the recipient thymus could recognize allogeneic HLA molecules. Recently it was shown that both naïve and memory CD4+ and CD8+ T cells are frequently cross-reactive against allogeneic HLA molecules and that this allorecognition exhibits exquisite peptide and HLA specificity and is dependent on both public and private specificities of the T cell receptor. In this review we highlight new insights gained into the immunogenetics of allorecognition, with particular emphasis on how viral infection and vaccination may specifically activate allo-HLA reactive T cells. We also briefly discuss the potential for virus-specific T cell infusions to produce GvHD. The progress made in understanding the molecular basis of allograft rejection will hopefully be translated into improved allograft function and/or survival, and eventually tolerance induction.
  Immunogenetics 12/2011; 64(2):77-85. · 2.93 Impact Factor
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  Article: KIR-ligand mismatches are associated with reduced long-term graft survival in HLA-compatible kidney transplantation.

  J van Bergen, A Thompson, G W Haasnoot, J I Roodnat, J W de Fijter, F H J Claas, F Koning, I I N Doxiadis
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  ABSTRACT: Natural killer (NK) cells are cytotoxic lymphocytes of the innate immune system with the ability to detect HLA class I disparities via killer-cell immunoglobulin-like receptors (KIR). To test whether such KIR-ligand mismatches contribute to the rejection of human solid allografts, we did a retrospective cohort study of 397 HLA-DR-compatible kidney transplantations and determined the KIR and HLA genotypes of recipients and the HLA genotypes of donors. In transplantations compatible for HLA-A, HLA-B and HLA-DR (n = 137), in which a role for T cells and HLA antibodies in rejection was minimized, KIR-ligand mismatches were associated with an approximately 25% reduction in 10-year death-censored graft survival (p = 0.043). This effect was comparable to the effect of classical HLA-A and HLA-B incompatibility, and in HLA-A,-B-incompatible transplantations (n = 260) no significant additional effect of KIR-ligand mismatches was observed. Multivariate Cox regression analysis confirmed the effect of KIR-ligand mismatching as an independent risk factor in HLA-A,-B,-DR-compatible transplantations (hazard ratio 2.29, range 1.03-5.10, p = 0.043). This finding constitutes the first indication that alloreactive NK cells may thwart the success of HLA-compatible kidney transplantations, and suggests that suppression of NK-cell activity can improve the survival of such kidney grafts.
  American Journal of Transplantation 06/2011; 11(9):1959-64. · 6.39 Impact Factor
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  Article: Challenging the golden standard in defining donor-specific antibodies: does the solid phase assay meet the expectations?

  Y M Zoet, S H Brand-Schaaf, D L Roelen, A Mulder, F H J Claas, I I N Doxiadis
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  ABSTRACT: The purpose of the study was to compare three different methods defining donor-specific antibodies (DSA): complement-dependent cytotoxicity (CDC), the flow cytometry method (FCM), and a special for that purpose commercially available Luminex-based solid phase assay (SPA). A panel of human monoclonal antibodies (HuMabs) with well-defined human leukocyte antigen (HLA) specificities was used as antibody source and single HLA antigen expressing cell lines (SAL) were used as targets. Two methods yielded identical results (CDC and FCM). However, the SPA, the method by which solubilized HLA molecules from the SAL are captured by microspheres, showed two additional reactions which could not be explained, neither by the epitope recognized by the HuMab nor by the widely accepted sensitivity of the SPA methodology. These unexplained results suggest that by capturing solubilized HLA molecules on microspheres, conformational changes might occur. Positive results obtained by similar Luminex-based microsphere methods should be therefore taken with caution and the 'recognized' HLA antigens should not automatically be considered as unacceptable for transplantation.
  Tissue Antigens 03/2011; 77(3):225-8. · 2.59 Impact Factor
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  Article: Alloreactivity from human viral specific memory T-cells.

  L J A D'Orsogna, D L Roelen, I I N Doxiadis, F H J Claas
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  ABSTRACT: The mechanisms by which alloreactive memory T-cells are generated in non-sensitized individuals have begun to be elucidated. It is generally accepted that a very high level of crossreactivity is an essential feature of the T-cell receptor. Indeed it has recently been shown that alloreactivity from viral specific memory T-cells is far more common than predicted, 45% of viral specific T-cell clones were found to be allo-HLA crossreactive. In this overview the evidence for crossreactive alloresponses from human viral specific memory T-cells is discussed with special emphasis on the unexpected high frequency of these crossreactive responses, the peptide and tissue specificity of the responses, and the mechanistic insights gleaned from the elucidation of the crystal structure of an allo-HLA crossreactive viral specific TCR. The possible implications for clinical solid organ and bone marrow transplantation and tolerance induction will be discussed.
  Transplant Immunology 08/2010; 23(4):149-55. · 1.46 Impact Factor