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51. Pretransplant C3d-Fixing Donor-Specific Anti-HLA Antibodies Are Not Associated with Increased Risk for Kidney Graft Failure

Author

Kamburova, E.G., Wisse, B.W., Joosten, I., Allebes, W.A., Meer, A. van der, Hilbrands, L.B., Baas, M.C., Spierings, E., Hack, C.E., Reekum, F.E. van, Zuilen, A.D. van, Verhaar, M.C., Bots, M.L., Drop, A.C., Plaisier, L., Seelen, M.A., Sanders, J.S., Hepkema, B.G., Lambeck, A.J.A., Bungener, L.B., Roozendaal, C., Tilanus, M.G., Voorter, C.E.M., Wieten, L., Duijnhoven, E.M. van, Gelens, M.A., Christiaans, M.H., Ittersum, F.J. van, Nurmohamed, S.A., Lardy, N.M., Swelsen, W., Pant, Karlijn A.M.I. van der, Weerd, N.C. van der, Berge, I.J. Ten, Bemelman, F.J., Hoitsma, A.J., Boog, P.J. van der, Fijter, J.W. de, Betjes, M.G., Heidt, S., Roelen, D.L., Claas, F.H., Otten, H.G., Kamburova, E.G., Wisse, B.W., Joosten, I., Allebes, W.A., Meer, A. van der, Hilbrands, L.B., Baas, M.C., Spierings, E., Hack, C.E., Reekum, F.E. van, Zuilen, A.D. van, Verhaar, M.C., Bots, M.L., Drop, A.C., Plaisier, L., Seelen, M.A., Sanders, J.S., Hepkema, B.G., Lambeck, A.J.A., Bungener, L.B., Roozendaal, C., Tilanus, M.G., Voorter, C.E.M., Wieten, L., Duijnhoven, E.M. van, Gelens, M.A., Christiaans, M.H., Ittersum, F.J. van, Nurmohamed, S.A., Lardy, N.M., Swelsen, W., Pant, Karlijn A.M.I. van der, Weerd, N.C. van der, Berge, I.J. Ten, Bemelman, F.J., Hoitsma, A.J., Boog, P.J. van der, Fijter, J.W. de, Betjes, M.G., Heidt, S., Roelen, D.L., Claas, F.H., and Otten, H.G.

Abstract

Item does not contain fulltext

Published
2018

52. Differential effects of donor-specific HLA antibodies in living versus deceased donor transplant

Author

CTI Otten, Infection & Immunity, CDL Celdiagnostiek, CTI, MS Nefrologie, Circulatory Health, Nefro Vasculaire Geneeskunde, Regenerative Medicine and Stem Cells, Cardiovasculaire Epi Team 5, JC onderzoeksprogramma Cardiovasculaire Epidemiologie, MS Mondziekten/Kaakchirurgie, Kamburova, E. G., Wisse, B. W., Joosten, I., Allebes, W. A., van der Meer, A., Hilbrands, L. B., Baas, M. C., Spierings, E., Hack, C. E., van Reekum, F. E., van Zuilen, A. D., Verhaar, M. C., Bots, M. L., Drop, A. C.A.D., Plaisier, L., Seelen, M. A.J., Sanders, J. S.F., Hepkema, B. G., Lambeck, A. J.A., Bungener, L. B., Roozendaal, C., Tilanus, M. G.J., Voorter, C. E., Wieten, L., van Duijnhoven, E. M., Gelens, M., Christiaans, M. H.L., van Ittersum, F. J., Nurmohamed, S. A., Lardy, N. M., Swelsen, W., van der Pant, K. A., van der Weerd, N. C., ten Berge, I. J.M., Bemelman, F. J., Hoitsma, A., van der Boog, P. J.M., de Fijter, J. W., Betjes, M. G.H., Heidt, S., Roelen, D. L., Claas, F. H., Otten, H. G., CTI Otten, Infection & Immunity, CDL Celdiagnostiek, CTI, MS Nefrologie, Circulatory Health, Nefro Vasculaire Geneeskunde, Regenerative Medicine and Stem Cells, Cardiovasculaire Epi Team 5, JC onderzoeksprogramma Cardiovasculaire Epidemiologie, MS Mondziekten/Kaakchirurgie, Kamburova, E. G., Wisse, B. W., Joosten, I., Allebes, W. A., van der Meer, A., Hilbrands, L. B., Baas, M. C., Spierings, E., Hack, C. E., van Reekum, F. E., van Zuilen, A. D., Verhaar, M. C., Bots, M. L., Drop, A. C.A.D., Plaisier, L., Seelen, M. A.J., Sanders, J. S.F., Hepkema, B. G., Lambeck, A. J.A., Bungener, L. B., Roozendaal, C., Tilanus, M. G.J., Voorter, C. E., Wieten, L., van Duijnhoven, E. M., Gelens, M., Christiaans, M. H.L., van Ittersum, F. J., Nurmohamed, S. A., Lardy, N. M., Swelsen, W., van der Pant, K. A., van der Weerd, N. C., ten Berge, I. J.M., Bemelman, F. J., Hoitsma, A., van der Boog, P. J.M., de Fijter, J. W., Betjes, M. G.H., Heidt, S., Roelen, D. L., Claas, F. H., and Otten, H. G.

Published
2018

53. Differential effects of donor-specific HLA antibodies in living versus deceased donor transplant

Author

Kamburova, E G, Wisse, B W, Joosten, I, Allebes, WA, Meer, A, Hilbrands, LB, Baas, M C, Spierings, E, Hack, CE, van Reekum, F E, van Zuilen, AD, Verhaar, MC, Bots, ML, Drop, A, Plaisier, L, Seelen, MAJ, Sanders, JSF, Hepkema, BG, Lambeck, AJA, Bungener, LB, Roozendaal, C, Tilanus, MGJ, Voorter, CE, Wieten, L, van Duijnhoven, E M, Gelens, M, Christiaans, MHL, van Ittersum, FJ, Nurmohamed, SA, Lardy, NM, Swelsen, W, van der Pant, K A, van der Weerd, NC, ten Berge, IJM, Bemelman, FJ, Hoitsma, A, van der Boog, P J M, de Fijter, JW, Betjes, M.G.H., Heidt, S, Roelen, DL, Claas, FH, Otten, HG, Kamburova, E G, Wisse, B W, Joosten, I, Allebes, WA, Meer, A, Hilbrands, LB, Baas, M C, Spierings, E, Hack, CE, van Reekum, F E, van Zuilen, AD, Verhaar, MC, Bots, ML, Drop, A, Plaisier, L, Seelen, MAJ, Sanders, JSF, Hepkema, BG, Lambeck, AJA, Bungener, LB, Roozendaal, C, Tilanus, MGJ, Voorter, CE, Wieten, L, van Duijnhoven, E M, Gelens, M, Christiaans, MHL, van Ittersum, FJ, Nurmohamed, SA, Lardy, NM, Swelsen, W, van der Pant, K A, van der Weerd, NC, ten Berge, IJM, Bemelman, FJ, Hoitsma, A, van der Boog, P J M, de Fijter, JW, Betjes, M.G.H., Heidt, S, Roelen, DL, Claas, FH, and Otten, HG

Abstract

The presence of donor-specific anti-HLA antibodies (DSAs) is associated with increased risk of graft failure after kidney transplant. We hypothesized that DSAs against HLA class I, class II, or both classes indicate a different risk for graft loss between deceased and living donor transplant. In this study, we investigated the impact of pretransplant DSAs, by using single antigen bead assays, on long-term graft survival in 3237 deceased and 1487 living donor kidney transplants with a negative complement-dependent crossmatch. In living donor transplants, we found a limited effect on graft survival of DSAs against class I or II antigens after transplant. Class I and II DSAs combined resulted in decreased 10-year graft survival (84% to 75%). In contrast, after deceased donor transplant, patients with class I or class II DSAs had a 10-year graft survival of 59% and 60%, respectively, both significantly lower than the survival for patients without DSAs (76%). The combination of class I and II DSAs resulted in a 10-year survival of 54% in deceased donor transplants. In conclusion, class I and II DSAs are a clear risk factor for graft loss in deceased donor transplants, while in living donor transplants, class I and II DSAs seem to be associated with an increased risk for graft failure, but this could not be assessed due to their low prevalence.

Published
2018

57. How can we reduce costs of solid-phase multiplex-bead assays used to determine anti-HLA antibodies?

Author

Kamburova, E.G., Wisse, B.W., Joosten, I., Allebes, W.A., Meer, A. van der, Hilbrands, L.B., Baas, M.C., Spierings, E., Hack, C.E., Reekum, F.E. van, Zuilen, A.D. van, Verhaar, M., Bots, M.L., Drop, A.C.A.D., Plaisier, L., Seelen, M.A.J., Sanders, J.S.F., Hepkema, B.G., Lambeck, A.J., Bungener, L.B., Roozendaal, C., Tilanus, M.G.J., Vanderlocht, J., Voorter, C.E., Wieten, L., Duijnhoven, E.M. van, Gelens, M., Christiaans, M.H.L., Ittersum, F.J. van, Nurmohamed, A., Lardy, N.M., Swelsen, W., Pant, K.A. van der, Weerd, N.C. van der, Berge, I.J.M. ten, Bemelman, F.J., Hoitsma, A., Boog, P.J.M. van der, Fijter, J.W. de, Betjes, M.G.H., Heidt, S., Roelen, D.L., Claas, F.H., Otten, H.G., RS: GROW - R3 - Innovative Cancer Diagnostics & Therapy, Interne Geneeskunde, MUMC+: DA Transplantatie Immunologie (5), MUMC+: DA TI Staf (9), MUMC+: DA TI Laboratorium (9), MUMC+: MA Nefrologie (9), RS: NUTRIM - R3 - Chronic inflammatory disease and wasting, Internal medicine, Nephrology, ICaR - Ischemia and repair, Internal Medicine, Other departments, AII - Amsterdam institute for Infection and Immunity, Groningen Institute for Organ Transplantation (GIOT), and Groningen Kidney Center (GKC)

Subjects
CLINICAL-RELEVANCE, KIDNEY-TRANSPLANTATION, Immunology, Other Research Radboud Institute for Molecular Life Sciences [Radboudumc 0], Sensitivity and Specificity, HLA Antigens, Isoantibodies, Genetics, Journal Article, Immunology and Allergy, Humans, Alleles, Automation, Laboratory, Immunoassay, Observer Variation, ALLOANTIBODIES, Histocompatibility Testing, Immune Sera, Reproducibility of Results, human leukocyte antigen antibodies, Kidney Transplantation, single antigen, solid-phase multiplex-bead assays, luminex, Reagent Kits, Diagnostic, Renal disorders Radboud Institute for Health Sciences [Radboudumc 11], Inflammatory diseases Radboud Institute for Molecular Life Sciences [Radboudumc 5]
Abstract

Item does not contain fulltext Solid-phase multiplex-bead assays are widely used in transplantation to detect anti-human leukocyte antigen (HLA) antibodies. These assays enable high resolution detection of low levels of HLA antibodies. However, multiplex-bead assays are costly and yield variable measurements that limit the comparison of results between laboratories. In the context of a Dutch national Consortium study we aimed to determine the inter-assay and inter-machine variability of multiplex-bead assays, and we assessed how to reduce the assay reagents costs. Fifteen sera containing a variety of HLA antibodies were used yielding in total 7092 median fluorescence intensities (MFI) values. The inter-assay and inter-machine mean absolute relative differences (MARD) of the screening assay were 12% and 13%, respectively. The single antigen bead (SAB) inter-assay MARD was comparable, but showed a higher lot-to-lot variability. Reduction of screening assay reagents to 50% or 40% of manufacturers' recommendations resulted in MFI values comparable to 100% of the reagents, with an MARD of 12% or 14%, respectively. The MARD of the 50% and 40% SAB assay reagent reductions were 11% and 22%, respectively. From this study, we conclude that the reagents can be reliably reduced at least to 50% of manufacturers' recommendations with virtually no differences in HLA antibody assignments.

Published
2016
Full Text
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58. What is wrong with the regulatory T cells and foetomaternal tolerance in women with recurrent miscarriages?

Author

Craenmehr, M.H.C., Heidt, S., Eikmans, M., and Claas, F.H.J.

Subjects
immune system, regulatory T cell, tolerance, pregnancy, recurrent miscarriage
Abstract

Couples of whom the woman has had a miscarriage have two major concerns: the cause and possible risk of recurrence. Unfortunately, a significant proportion of cases of recurrent miscarriage (RM) remain unexplained despite detailed investigation. Because data suggest that regulatory T cells (Treg) are involved in the maternal acceptance of the allogeneic foetus, RMcould possibly be explained by a disturbance of the Treg network. The possible role of Tregs in RM is described in this review, as well as their potential application in diagnostics and therapeutic intervention trials. Couples of whom the woman has had a miscarriage have two major concerns: the cause and possible risk of recurrence. Unfortunately, a significant proportion of cases of recurrent miscarriage (RM) remain unexplained despite detailed investigation. Because data suggest that regulatory T cells (Treg) are involved in the maternal acceptance of the allogeneic foetus, RMcould possibly be explained by a disturbance of the Treg network. The possible role of Tregs in RM is described in this review, as well as their potential application in diagnostics and therapeutic intervention trials.

Published
2016

66. How can we reduce costs of solid-phase multiplex-bead assays used to determine anti-HLA antibodies?

Author

Kamburova, E. G., Wisse, B. W., Joosten, I., Allebes, W. A., van der Meer, A., Hilbrands, L. B., Baas, M. C., Spierings, E., Hack, C. E., van Reekum, F. E., van Zuilen, A. D., Verhaar, M., Bots, M. L., Drop, A. C A D, Plaisier, L., Seelen, M. A J, Sanders, J. S F, Hepkema, B. G., Lambeck, A. J., Bungener, L. B., Roozendaal, C., Tilanus, M. G J, Vanderlocht, J., Voorter, C. E., Wieten, L., van Duijnhoven, E. M., Gelens, M., Christiaans, M. H L, van Ittersum, F. J., Nurmohamed, A., Lardy, N. M., Swelsen, W., van der Pant, K. A., van der Weerd, N. C., ten Berge, I. J M, Bemelman, F. J., Hoitsma, A., van der Boog, P. J M, de Fijter, J. W., Betjes, M. G H, Heidt, S., Roelen, D. L., Claas, F. H., Otten, H. G., Kamburova, E. G., Wisse, B. W., Joosten, I., Allebes, W. A., van der Meer, A., Hilbrands, L. B., Baas, M. C., Spierings, E., Hack, C. E., van Reekum, F. E., van Zuilen, A. D., Verhaar, M., Bots, M. L., Drop, A. C A D, Plaisier, L., Seelen, M. A J, Sanders, J. S F, Hepkema, B. G., Lambeck, A. J., Bungener, L. B., Roozendaal, C., Tilanus, M. G J, Vanderlocht, J., Voorter, C. E., Wieten, L., van Duijnhoven, E. M., Gelens, M., Christiaans, M. H L, van Ittersum, F. J., Nurmohamed, A., Lardy, N. M., Swelsen, W., van der Pant, K. A., van der Weerd, N. C., ten Berge, I. J M, Bemelman, F. J., Hoitsma, A., van der Boog, P. J M, de Fijter, J. W., Betjes, M. G H, Heidt, S., Roelen, D. L., Claas, F. H., and Otten, H. G.

Published
2016

67. How can we reduce costs of solid-phase multiplex-bead assays used to determine anti-HLA antibodies?

Author

CTI Otten, Infection & Immunity, CDL Celdiagnostiek, CTI, Lab exp immunologie / biomarkers ontst., MS Nefrologie, Circulatory Health, Nefro Vasculaire Geneeskunde, Regenerative Medicine and Stem Cells, Cardiovasculaire Epi Team 5, JC onderzoeksprogramma Cardiovasculaire Epidemiologie, Kamburova, E. G., Wisse, B. W., Joosten, I., Allebes, W. A., van der Meer, A., Hilbrands, L. B., Baas, M. C., Spierings, E., Hack, C. E., van Reekum, F. E., van Zuilen, A. D., Verhaar, M., Bots, M. L., Drop, A. C A D, Plaisier, L., Seelen, M. A J, Sanders, J. S F, Hepkema, B. G., Lambeck, A. J., Bungener, L. B., Roozendaal, C., Tilanus, M. G J, Vanderlocht, J., Voorter, C. E., Wieten, L., van Duijnhoven, E. M., Gelens, M., Christiaans, M. H L, van Ittersum, F. J., Nurmohamed, A., Lardy, N. M., Swelsen, W., van der Pant, K. A., van der Weerd, N. C., ten Berge, I. J M, Bemelman, F. J., Hoitsma, A., van der Boog, P. J M, de Fijter, J. W., Betjes, M. G H, Heidt, S., Roelen, D. L., Claas, F. H., Otten, H. G., CTI Otten, Infection & Immunity, CDL Celdiagnostiek, CTI, Lab exp immunologie / biomarkers ontst., MS Nefrologie, Circulatory Health, Nefro Vasculaire Geneeskunde, Regenerative Medicine and Stem Cells, Cardiovasculaire Epi Team 5, JC onderzoeksprogramma Cardiovasculaire Epidemiologie, Kamburova, E. G., Wisse, B. W., Joosten, I., Allebes, W. A., van der Meer, A., Hilbrands, L. B., Baas, M. C., Spierings, E., Hack, C. E., van Reekum, F. E., van Zuilen, A. D., Verhaar, M., Bots, M. L., Drop, A. C A D, Plaisier, L., Seelen, M. A J, Sanders, J. S F, Hepkema, B. G., Lambeck, A. J., Bungener, L. B., Roozendaal, C., Tilanus, M. G J, Vanderlocht, J., Voorter, C. E., Wieten, L., van Duijnhoven, E. M., Gelens, M., Christiaans, M. H L, van Ittersum, F. J., Nurmohamed, A., Lardy, N. M., Swelsen, W., van der Pant, K. A., van der Weerd, N. C., ten Berge, I. J M, Bemelman, F. J., Hoitsma, A., van der Boog, P. J M, de Fijter, J. W., Betjes, M. G H, Heidt, S., Roelen, D. L., Claas, F. H., and Otten, H. G.

Published
2016

74. The impact of Th17 cells on transplant rejection and the induction of tolerance

Author

Heidt, S, Segundo, DS, San, D, Chadha, R, and Wood, KJ

Subjects
Graft Rejection, Isoantigens, Cellular differentiation, chemical and pharmacologic phenomena, Context (language use), Tregs, Biology, T-Lymphocytes, Regulatory, Article, medicine, Animals, Humans, Transplantation, Homologous, Immunology and Allergy, Immunosuppression Therapy, Transplantation, Graft Survival, Interleukin-17, Cell Differentiation, hemic and immune systems, T-Lymphocytes, Helper-Inducer, medicine.disease, Transplant rejection, IL-17, plasticity, Immunology, Transplantation Tolerance, Graft survival, Inflammation Mediators, rejection
Abstract

PURPOSE OF REVIEW: This review aims to provide an overview of the latest evidence for the involvement of Th17 cells in the rejection of solid organ allografts. It will also consider the implications of the relationship between the differentiation pathways of Th17 and regulatory T cells (Tregs), as well as their plasticity in the context of transplantation tolerance. RECENT FINDINGS: In the absence of the Th1 lineage in vivo, Th17 cells are capable of rejecting cardiac allografts, showing the capacity of Th17 cells to cause allograft rejection, at least in experimental models. Th17 cells are relatively unsusceptible to suppression by Tregs, although this may be context dependent. Furthermore, addition of inflammatory signals to a Treg-inducing environment leads to Th17 development and established Tregs can be converted to Th17 cells under inflammatory conditions. SUMMARY: The capacity of Th17 cells to cause allograft rejection is becoming increasingly clear. However, the role and contribution of Th17 cells in allograft rejection in the presence of the full orchestra of T helper cells remains elusive. The apparent resistance of Th17 to be suppressed by Tregs may pose a hurdle for effective immunosuppression and tolerance inducing protocols. Furthermore, the close developmental pathways of Th17 and Tregs and the ability of Tregs to convert into Th17 cells in the presence of inflammatory signals may impede the establishment of specific unresponsiveness to donor alloantigens in vivo.

Published
2010

75. Characterization of B cell responses in relation to organ transplantation

Author

Heidt, S., Claas, F.H.J., Brand, A., Mulder, A., Roelen, D.L., and Leiden University

Subjects
Transplantation, B cells, Monitoring, Immunosuppressive drugs, Humoral rejection
Abstract

Antibody-mediated rejection is increasingly recognised within the transplantation community as a cause or contributing factor in the rejection of transplanted organs. The humoral immune response towards allografts involves B cells that, after T cell dependent activation, can differentiate into antibody producing cells. Whereas there are several therapeutic entities to treat cellular rejection, at present, no standard treatment for humoral rejection exists. The first part of this thesis describes the effects of different maintenance immunosuppressive drugs directly on B cells, as well as the effect on T cell help in vitro. The data presented in these chapters show differential effects of the drugs on B cells and T cell help. Furthermore, the effects of novel, experimental drugs on the in vitro activation of B cells are described. The second part of this thesis describes the development of a novel technique for monitoring the humoral alloimmune response. By using this technique, patients at risk for humoral rejection may be identified. The last part describes the difficulties and pitfalls of monitoring T cells that respond to alloantigen via the indirect pathway of allorecognition. In an alloimmune response, these are the T cells that provide help to B cells to become fully activated.

Published
2010

80. Differential effects of donor‐specific HLAantibodies in living versus deceased donor transplant

Author

Kamburova, E. G., Wisse, B. W., Joosten, I., Allebes, W. A., Meer, A., Hilbrands, L. B., Baas, M. C., Spierings, E., Hack, C. E., Reekum, F. E., Zuilen, A. D., Verhaar, M. C., Bots, M. L., Drop, A. C. A. D., Plaisier, L., Seelen, M. A. J., Sanders, J. S .F., Hepkema, B. G., Lambeck, A. J. A., Bungener, L. B., Roozendaal, C., Tilanus, M. G. J., Voorter, C. E., Wieten, L., Duijnhoven, E. M., Gelens, M., Christiaans, M. H. L., Ittersum, F. J., Nurmohamed, S. A., Lardy, N. M., Swelsen, W., Pant, K. A., Weerd, N. C., Berge, I. J. M., Bemelman, F. J., Hoitsma, A., Boog, P. J. M., Fijter, J. W., Betjes, M. G. H., Heidt, S., Roelen, D. L., Claas, F. H., and Otten, H. G.

Abstract

The presence of donor‐specific anti‐HLAantibodies (DSAs) is associated with increased risk of graft failure after kidney transplant. We hypothesized that DSAsagainst HLAclass I, class II,or both classes indicate a different risk for graft loss between deceased and living donor transplant. In this study, we investigated the impact of pretransplant DSAs, by using single antigen bead assays, on long‐term graft survival in 3237 deceased and 1487 living donor kidney transplants with a negative complement‐dependent crossmatch. In living donor transplants, we found a limited effect on graft survival of DSAsagainst class I or IIantigens after transplant. Class I and II DSAscombined resulted in decreased 10‐year graft survival (84% to 75%). In contrast, after deceased donor transplant, patients with class I or class II DSAshad a 10‐year graft survival of 59% and 60%, respectively, both significantly lower than the survival for patients without DSAs(76%). The combination of class I and II DSAsresulted in a 10‐year survival of 54% in deceased donor transplants. In conclusion, class I and II DSAsare a clear risk factor for graft loss in deceased donor transplants, while in living donor transplants, class I and II DSAsseem to be associated with an increased risk for graft failure, but this could not be assessed due to their low prevalence. Via a retrospective multicenter study, the authors investigate the impact of pretransplant donor‐specific HLA antibodies on long‐term graft survival in deceased and living donor kidney transplantations.

Published
2018
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81. Je nier of mijn leven

Author

Ambagtsheer, J. A. E., Bemelman, F. J., Berger, P., Evers, A. W. M., den Hartogh, G. A., Heidt, S., Hilbrands, L. B., Hoitsma, A., Janki, S., van Middendorp, H., Wirken, L., Ijzermans, J. N. M., Zuidema, W. C., Geraerdts, J. P. M., van Bekkum, D. W., van Haren, W., Amsterdam institute for Infection and Immunity, and Nephrology

Published
2002

90. Towards HLA epitope matching in clinical transplantation

Author

Kramer, C.S.M., Claas, F.H.J., Heidt, S., Roelen, D.L., Kooten, C. van, Reinders, M.E.J., Tambur, A.R., Naesens, M., and Leiden University

Subjects
HLA, Kidney transplantation, HLA-EMMA, Donor-specific antibodies, B cell epitope, Antibody-verification eplets, Matching, Recombinant human monoclonal antibodies, Antigenicity, Immunogenicity
Abstract

In recent years HLA epitope matching is becoming a hot topic in transplant community to prevent donor-specific antibody formation after transplantation, as such antibodies are associated with inferior graft survival. The number of HLA epitope mismatches between donor and recipient correlates with donor-specific antibody formation, but not every epitope mismatch will trigger an antibody response. Therefore, it is pivotal to define the immunogenic epitopes. In my thesis we describe the development of the software HLA-EMMA to determine HLA amino acid mismatches between donor and recipient to identify immunogenic amino acids. In addition, the generation of recombinant human HLA-DR monoclonal antibodies for antibody-verification of eplets/epitopes is described. These tools will contribute to the definition of immunogenic epitopes, which is required before introducing HLA epitope matching in the clinic.

Published
2020

91. Immune parameters affecting maternal tolerance towards the fetus in normal and aberrant pregnancies

Author

Craenmehr, M.H.C., Claas, F.H.J., Eikmans, M., Heidt, S., Jager, M.J., Bloemenkamp, K.W.M., Scherjon, S.A., and Leiden University

Subjects
Human Leukocyte Antigen (HLA), Pregnancy complications, Pregnancy, Maternal immune response, Placenta, Immunology, Tolerance, Recurrent miscarriage
Abstract

Pregnancy can be seen as an immunologic paradox. Even though the fetus expresses paternally inherited alloantigens it is protected from rejection by a proper regulation of the maternal immune system. With the studies described in this thesis, we want to get more insight in the immunologic mechanisms that play a role in pregnancy. The results of this research can help to identify underlying etiologies in patients with unexplained pregnancy complications, such as recurrent miscarriage. Identifying these causes is important for providing answers and taking away anxiety in these couples, and eventually for the development of effective therapies. Furthermore, elucidating the mechanism leading to survival or rejection of the fetal allograft is not only essential for our understanding of processes leading to normal and abnormal pregnancies, but may also result in important concepts in the field of transplantation and autoimmunity.

Published
2020

92. The immune compartment at the maternal-fetal interface throughout human pregnancy

Author

Zwan, A. van der, Claas, F.H.J., Heidt, S., Tilburgs, T., Borts, J., Kooten, C. van, Moffett, A., Saito, S., and Leiden University

Subjects
T cell exhaustion, Heterologous immunity, HLA-C, Pregnancy, Placenta, Immunology, Decidua, Regulatory T cells, Tolerance, Trophoblasts
Abstract

During pregnancy a unique situation arises in which the mother's immune system accepts the fetus, which carries both maternal and paternal genes, and does not reject it as can occur in solid organ transplantation. The aim of this dissertation was to unravel the immunological mechanisms that ensure tolerance during a healthy pregnancy and uncover how alterations could contribute to the development of pregnancy complications, such as pre-eclampsia and preterm birth.We applied the new technique mass cytometry and the associated computational analyzes to map all immune cells of the mother during a healthy pregnancy. Furthermore, we demonstrated the presence of three types of functional regulatory CD4+ T cells, identified a phenotype of CD8+ T cells that can offer both tolerance and immunity against infections, and demonstrated potential cross-reactivity of T cells against fetal allo-antigens. The results described in this thesis have contributed to a better understanding of healthy pregnancies and form a basis on which further research can be built.

Published
2020

93. Paternal factors in recurrent miscarriage : a role beyond conception

Author

Meuleman, T., Claas, F.H.J., Lith, J.M.M. van, Koning, F., Robertson, S., Joosten, I, Heidt, S., and Leiden University

Subjects
Immunomodulation, HLA-C, Classical complement system, Pregnancy, Immunology, HLA-G, HLA antibodies, humanities, Humoral rejection, Seminal plasma, Recurrent miscarriage
Abstract

In normal pregnancy the fetus, although a semi-allograft, is tolerated by the maternal immune system. It has been suggested that an inadequate maternal allo-immune response to the paternal antigens of the fetus is responsible for a proportion of the unexplained recurrent miscarriage. In chapter 2 we provide an overview on the possible role of the HLA system in recurrent miscarriage. No consistent conclusions can be drawn since the observed odd ratios found were relatively small and the risk of bias in the selected studies was high. In chapter 3 we compared the genetic polymorphisms of HLA-G in women with recurrent miscarriage with women with uneventful pregnancy. The HLA-G UTR-4 haplotype was less frequently observed in women with recurrent miscarriage, suggesting an immunoregulatory role of this haplotype. The combined results from chapter 4, chapter 6 and chapter 7 suggest that in a portion of women with unexplained recurrent miscarriage antibody-mediated rejection of the fetal allograft may play a role. We showed in chapter 8 that human seminal plasma contains all kinds of immunoregulatory factors and has an immunomodulatory effect on T cells. In chapter 9 a matched case-control study practicing oral sex was negatively associated with the occurrence of recurrent miscarriage.

Published
2018

94. HLA-specific memory B cells : the missing link?

Author

Karahan, G.E., Claas, F.H.J., Heidt, S., Koning, F., Hilbrands, L., Fuggle, S., and Leiden University

Subjects
HLA, Transplantation, Memory B cells, Antibody
Abstract

The aim of this thesis was to develop tools to detect and quantify HLA-specific memory B cells in peripheral blood of HLA-immunized individuals and to assess the applicability of the newly developed assays in the setting of clinical transplantation. Transplant patients who have already made a defense response to the foreign HLA on donor organ have an increased risk of developing antibody-mediated rejection, which may adversely affect the survival of the graft. In diagnostic HLA laboratories, serum of the patients is tested for the presence of HLA-specific antibodies before and after transplantation. Serum HLA antibodies are produced by plasma cells located in the bone marrow however, memory B cells can also play a role in antibody production against the donor organ. So far, the role of these cells has been neglected in the diagnostics. The research conducted in my PhD thesis enabled us to develop methods to detect HLA-specific memory B cells. By this means, patients who may potentially harbor HLA-specific memory B cells such as repeat transplant candidates, women receiving transplants from their partner or child and patients undergoing desensitization treatments may benefit from the assays that are described in this PhD thesis.

Published
2017

96. Chimeric HLA antibody receptor T cell therapy for humoral transplant rejection.

Author

Arana C, Garcia-Busquets A, Nicoli M, Betriu S, Gille I, Heemskerk MHM, Heidt S, Palou E, Rovira J, and Diekmann F

Subjects
Humans, Receptors, Chimeric Antigen immunology, Immunity, Humoral, Organ Transplantation adverse effects, T-Lymphocytes immunology, Receptors, Antigen, T-Cell immunology, Receptors, Antigen, T-Cell genetics, Graft Rejection immunology, Graft Rejection therapy, Graft Rejection prevention & control, HLA Antigens immunology
Abstract

Antibody-mediated rejection (ABMR) is a significant obstacle to achieving optimal long-term outcomes after solid organ transplantation. The presence of donor-specific antibodies (DSAs), particularly against human leucocyte antigen (HLA), increases the risk of allograft rejection and subsequent graft loss. No effective treatment for ABMR currently exists, warranting novel approaches to target the HLA-specific humoral alloimmune response. Cellular therapies may hold promise to this end. According to publicly available sources as of now, three independent laboratories have genetically engineered a chimeric HLA antibody receptor (CHAR) and transduced it into human T cells, based on the demonstrated efficacy of chimeric antigen receptor T cell therapies in malignancies. These CHAR-T cells are designed to exclusively eliminate B cells that produce donor-specific HLA antibodies, which form the cornerstone of ABMR. CHAR technology generates potent and functional human cytotoxic T cells to target alloreactive HLA-specific B cells, sparing B cells with other specificities. Thus CHAR technology may be used as a selective desensitization protocol and to treat ABMR after solid organ transplantation., (© The Author(s) 2024. Published by Oxford University Press on behalf of the ERA.)

Published
2024
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97. Allogenic MSC infusion in kidney transplantation recipients promotes within 4 hours distinct B cell and T cell phenotypes.

Author

Hendriks SH, Heidt S, Reinders MEJ, Koning F, and van Kooten C

Subjects
Humans, Female, Male, Middle Aged, Adult, T-Lymphocytes immunology, Phenotype, Mesenchymal Stem Cells immunology, Immunophenotyping, Transplantation, Homologous, Aged, Kidney Transplantation, Mesenchymal Stem Cell Transplantation methods, B-Lymphocytes immunology
Abstract

Background: Infusion of mesenchymal stromal cells (MSCs) has been proposed as immune-modulatory therapy in solid organ transplantation. The use of allogenic MSCs could improve standardization and allow for direct availability of the product., Method: The nonrandomized phase Ib Neptune clinical trial provided safety and feasibility data on the use of allogenic bone-marrow-derived MSCs, infused in 10 patients at week 25 and 26 post kidney transplantation. Here, we performed detailed analysis on the peripheral blood immune cell composition of these patients up to 52 weeks post transplantation. We used a 40 marker antibody panel with mass cytometry to assess potential effects of MSC therapy on the immune system., Results: We showed minor changes in major immune lineages at week 27, 34 and 52 post kidney transplantation after MSC infusion at week 25 and week 26, confirming previous data with regular flow cytometry. However, in a direct comparison between pre- and post MSC infusion, as soon as 4 hours after MSC infusion, we observed a significant increase in cell numbers of B cell and T cell subsets that shared a unique expression of CD11b, CD11c, CD38, CD39, and Ki-67., Conclusion: Exploring these CD11b + CD11c + CD38 + CD39 + Ki-67 + B cells and T cells in the context of MSC infusion after kidney transplantation may be a promising avenue to better understand the immunological effects of MSC therapy., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. The author(s) declared that they were an editorial board member of Frontiers, at the time of submission. This had no impact on the peer review process and the final decision., (Copyright © 2024 Hendriks, Heidt, Reinders, Koning and van Kooten.)

Published
2024
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98. Allogeneic mesenchymal stromal cell therapy in kidney transplantation: should repeated human leukocyte antigen mismatches be avoided?

Author

Bezstarosti S, Erpicum P, Maggipinto G, Dreyer GJ, Reinders MEJ, Meziyerh S, Roelen DL, De Fijter JW, Kers J, Weekers L, Beguin Y, Jouret F, and Heidt S

Abstract

Mesenchymal stromal cells (MSCs) have immunomodulatory properties and are therefore considered promising tools in kidney transplantation. Although most studies have been conducted with autologous MSCs, using allogeneic MSCs as an off-the-shelf product is more feasible in clinical settings. However, allogeneic MSCs could potentially induce an immune response, which might eventually be directed towards the kidney allograft because of shared human leukocyte antigen (HLA) epitope mismatches between the kidney and MSC donor. In this study, we performed in-depth analyses of two cohorts (n = 20) that received third-party MSC therapy after kidney transplantation. While the Neptune Study from Leiden University Medical Center specifically selected MSC to avoid repeated HLA antigen mismatches between kidney and MSC donors, the study from the University of Liège did not perform specific MSC selection. The comparative analyses of amino acid mismatches between these cohorts showed that MSC selection to avoid repeated HLA mismatches at the split antigen level was not sufficient to prevent repeated mismatches at the amino acid level. However, repeated amino acid mismatches were not associated with the occurrence of donor-specific antibodies (DSAs). Thus, the clinical relevance of repeated amino acid mismatches seems to be limited with regard to the risk of DSA formation. Since DSA formation was limited (3 of 20 patients) in this study, larger studies are required to investigate the relevance of preventing repeated HLA mismatches in allogeneic MSC therapy in kidney transplantation., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2024 Bezstarosti, Erpicum, Maggipinto, Dreyer, Reinders, Meziyerh, Roelen, De Fijter, Kers, Weekers, Beguin, Jouret and Heidt.)

Published
2024
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99. Permissible HLA mismatches in 9/10 unrelated donor pediatric stem cell transplants using HLA-EMMA: an EBMT Inborn Errors Working Party study.

Author

von Asmuth EGJ, Hiensch F, Heidt S, Mohseny AB, Roelen DL, Kramer CSM, Claas FHJ, Albert MH, Neven B, Lankester AC, and van Beek AA

Subjects
Humans, Child, Child, Preschool, Male, Female, Adolescent, Infant, Graft vs Host Disease etiology, Transplantation, Homologous, Unrelated Donors, Hematopoietic Stem Cell Transplantation methods, Histocompatibility Testing, HLA Antigens immunology
Abstract

Abstract: Allogeneic hematopoietic stem cell transplantation (HSCT) with mismatched unrelated donors (MMUD) is associated with inferior outcome compared with matched unrelated donors (MUDs). We aimed to identify permissible mismatches using HLA epitope mismatch algorithm, which determines permissibility by analyzing amino acid sequences, in a single-center cohort of 70 pediatric 9/10 MMUD HSCTs and 157 10/10 MUDs for comparison. Amino acid matching was evaluated for the whole HLA protein, the α-helices, and the β-sheets, in both host vs graft (HvG) and graft vs host (GvH) direction. Superior event-free survival (EFS) was found in 13 patients permissibly mismatched in the HvG direction (totalHvG, 92% vs 58% at 1 year; P = .009) and in 21 patients matched on the α-helices (αHvG, 90% vs 53%; P = .002). These rates were similar to EFS rates in patients with 10/10 MUDs (90% vs 80%; P = .60). EFS was not related to β-sheet amino acid matching, nor to matching in the GvH direction. Overall survival (OS) rates trended similarly to those of EFS for amino acid mismatches (totalHvG, 92% vs 74%; P = .075; αHvG, 90% vs 71%; P = .072). These findings were reproduced in an EBMT Registry inborn errors cohort of 271 pediatric 9/10 MMUD HSCTs and 929 10/10 MUD HSCTs, showing a significant effect of αHvG matching on both OS and EFS and similar OS and EFS between αHvG matched MMUDs and 10/10 MUDs. In summary, HvG amino acid matching on the α-helices identifies 9/10 MMUDs with permissible mismatches, which are correlated with favorable transplant outcomes similar to those of matched donors., (© 2024 by The American Society of Hematology. Licensed under Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International (CC BY-NC-ND 4.0), permitting only noncommercial, nonderivative use with attribution. All other rights reserved.)

Published
2024
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100. Proficiency testing within Eurotransplant.

Author

Zoet YM, Heidt S, van der Linden-van Oevelen MJH, Haasnoot GW, and Claas FHJ

Abstract

Eurotransplant is responsible for the international allocation of organs between eight countries in Europe. All HLA laboratories affiliated to Eurotransplant must be EFI or ASHI-accredited and must participate in the Eurotransplant external proficiency testing (EPT) program, organized by the Eurotransplant Reference Laboratory (ETRL). EPT within Eurotransplant has a long tradition, starting in 1978. The current EPT program consists of the following schemes: HLA typing including serology, CDC crossmatching, HLA-specific antibody detection, and identification. Participants enter the results of laboratory tests using a web-based application. Assessed results are visible on the website. An additional component called "patient-based cases" runs since 2016. Results are summarized and published on the EPT website. Furthermore, these results are discussed during the annual extramural tissue typers meeting, which is organized by the ETRL. Thanks to this EPT program, the performance of all HLA laboratories affiliated to Eurotransplant can be monitored and corrected, if necessary. Because all affiliated laboratories are assessed in the same EPT program, where these laboratories show to be consistent in most of their results, Eurotransplant EPT has proven to be an efficient tool to create a more uniform level of quality of histocompatibility testing within Eurotransplant., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2024 Zoet, Heidt, van der Linden-van Oevelen, Haasnoot and Claas.)

Published
2024
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