Transplantation Immunology

Study of the immune response to CMV and BKV infection in these immuno-compromised patients provides insights that are also applicable to patients who are immuno-compromised for other reasons.

Ineke ten Berge, PhD

The research program Transplantation Immunology is focused on:

1) The presence and significance of virus-specific CD8+ T cells with cross-reactivity to alloantigen in kidney transplant recipients. First, we developed methods to detect cross-reactive cells and to characterize them functionally. Next, we studied their presence and function in healthy individuals and in renal transplant recipients. Our results indicate that circulating virus-specific T cells can indeed cross-react to alloantigens. In cytomegalovirus (CMV) seropositive recipients, cross-reactive T cells can exist prior to transplantation or emerge after viral reactivation. Donor-specific cross-reactive T cells appeared to be present in the circulation transiently, suggesting that they home to the graft. Therefore, we will study not only the peripheral-blood compartment, but also lymphocytes eluted from graft biopsies. Obtained data will be correlated to the clinical course of patients.

2) The immune response against CMV-infection in renal transplant recipients. Lymph nodes (LN) obtained from surgically removed iliac tissue of recipients of a kidney transplant appeared to contain CMV-specific CD8+ T cells resembling central memory cells, which are infrequent in peripheral blood (PB). Using next generation sequencing, the LN CMV-pp65-specific CD8+ T cell pool appeared to contain clones not found in PB. Since it is unknown if human LN CMV-specific CD8+ T cells contribute to the PB pool upon viral recall, we studied the possible appearance of these clones in the circulation during CMV reactivation. A diverse picture emerged, from which it could not be determined if the LN cells contributed to the vigorous expansion of the CMV-specific pool during reactivation. These studies will be continued and focus on heterogeneity of the T cell response in several lymphoid compartments during latency.

3) The immune response against BKV-infection in renal transplant recipients. Using different HLA-A02-tetramers, we developed methods to characterize circulating BKV-specific CD8+ T cells, essential in the defence against the virus. Phenotypic analysis showed that BKV-specific T cells in healthy individuals are mainly VP1-specific and can be considered as non-activated ‘effector memory’ T cells that express granzyme-K, but no other cytotoxic molecules. To assess the influence of BKV-specific cellular immune responses on the risk and development of BKV-nephropathy following renal transplantation, BKV-specific CD8+ T cells will be phenotypically and functionally characterized in renal transplant patients with or without this complication.

4) We previously showed that BKV-viremia is associated with induction of TLR3, MDA5, and RIG-I in tubular epithelium and that these dsRNA-sensors trigger an anti-viral and pro-apoptotic program in primary human tubular epithelial cells. Next, we aim to clarify the recognition of - and overall innate immune response to BKV, and to elucidate immune-evasive strategies of the virus. In addition, we will identify factors that facilitate viral (re)activation in renal epithelium and contribute to the development of BKV-nephropathy.

5) Optimization of immunosuppressive drug therapy in renal transplantation. As part of a new recently started clinical trial, immunological, vascular and pharmacological studies will be performed.

Group members

R.J.M. ten Berge, MD, PhD
F.J. Bemelman, MD, PhD 
K.A.M.I. van Donselaar, MD 
K.M. Heutinck, MSc, postdoc 
H. de Kort, postdoc
M.C. van Aalderen, MD, PhD
M. Nijland, MD, PhD 
G.H. Struijk, MD, PhD
E.B.M. Remmerswaal Ing, PhD
S.L. Yong

Selected publications

van Aalderen MC, Remmerswaal EB, Heutinck KM, ten Brinke A, Pircher H, van Lier RA, ten Berge IJ. Phenotypic and functional characterization of circulating polyomavirus BK VP1-specific CD8+ T cells in healthy adults. J Virol.2013;87:10263-72.

Havenith SH, Yong SL, Henson SM, Piet B, Idu MM, Koch SD, Jonkers RE, Kragten NA, Akbar AN, van Lier RA, ten Berge IJ. Analysis of stem-cell-like properties of human CD161++IL-18Rα+ memory CD8+ T cells. Int Immunol. 2012;24:625-36.

Heutinck KM, Rowshani AT, Kassies J, Claessen N, van Donselaar-van der Pant KAMI, Bemelman FJ, Eldering E, van Lier RAW, Florquin S, ten Berge IJM, Hamann J, Viral double-stranded RNA sensors induce antiviral, pro-inflammatory, and pro-apoptotic responses in human renal tubular epithelial cells. Kidney Int 2012; 82: 664-75.

Remmerswaal EB, Havenith SH, Idu MM, van Leeuwen EM, van Donselaar KA, Ten Brinke A, van der Bom-Baylon N, Bemelman FJ, van Lier RA, Ten Berge IJ. Human virus-specific effector-type T cells accumulate in blood but not in lymph nodes. Blood 2012;119:1702-12.

Hertoghs KM, Moerland PD, van Stijn A, Remmerswaal EB, Yong SL, van de Berg PJ, van Ham SM, Baas F, ten Berge IJ, van Lier RA. Molecular profiling of cytomegalovirus-induced human CD8+ T cell differentiation. J Clin Invest2010;120:4077-90.

Van de Berg PJ, Heutinck KM, Raabe R, Minnee RC, Young SL, van Donselaar-van der Pant KA, Bemelman FJ, van Lier RA, ten Berge IJ. Human cytomegalovirus induces systemic immune activation characterized by a type 1 cytokine signature. J Infect Dis 2010;202:690-9.

Van Leeuwen EM, Koning JJ, Remmerswaal EB, van Baarle D, van Lier RA, ten Berge IJ. Differential usage of cellular niches by cytomegalovirus versus EBV-and influenza virus-specific CD8+ T cells. J Immunol 2006;177:4998-5005.

Uss E, Rowshani AT, Hooibrink B, Lardy NM, van Lier RA, ten Berge IJ. CD103 is a marker for alloantigen-induced regulatory CD8+ T cells. J Immunol2006;177:2775-83.

Rowshani AT, Florquin S, Bemelman F, Kummer JA, Hack CE, Ten Berge IJ. Hyperexpression of the granzyme B inhibitor PI-9 in human renal allografts: a potential mechanism for stable renal function in patients with subclinical rejection. Kidney Int 2004;66:1417-22.

Van Leeuwen EM, Remmerswaal EB, Vossen MT, Rowshani AT, Wertheim-van Dillen PM, van Lier RA, ten Berge IJ. Emergence of a CD4+CD28- granzyme B+, cytomegalovirus-specific T cell subset after recovery of primary cytomegalovirus infection. J Immunol 2004;173:1834-41.

Gamadia LE, Remmerswaal EB, Weel JF, Bemelman F, van Lier RA, Ten Berge IJ. Primary immune responses to human CMV: a critical role for IFN-gamma-producing CD4+ T cells in protection against CMV disease. Blood 2003;101:2686-92.

Gamadia LE, ten Berge IJ, Picker LJ, van Lier RA. Skewed maturation of virus-specific CTLs? Nat Immunol 2002;3:203.

Rentenaar RJ, Gamadia LE, van DerHoek N, van Diepen FN, Boom R, Weel JF, Wertheim-van Dillen PM, van Lier RA, ten Berge IJ. Development of virus-specific CD4(+) T cells during primary cytomegalovirus infection. J Clin Invest2000;105:541-8.

Wever PC, Spaeny LH, van der Vliet HJ, Rentenaar RJ, Wolbink AM, Surachno J, Wertheim PM, Schellekens PT, Hack CE, ten Berge IJ. Expression of granzyme B during primary cytomegalovirus infection after renal transplantation. J Infect Dis1999;179:693-6.

Buysmann S, Bemelman FJ, Schellekens PT, van Kooyk Y, Figdor CG, ten Berge IJ. Activation and increased expression of adhesion molecules on peripheral blood lymphocytes is a mechanism for the immediate lymphocytopenia after administration of OKT3. Blood 1996;87:404-11.

Bemelman FJ, Buysmann S, Surachno J, Wilmink JM, Schellekens PT, ten Berge IJ. Pretreatment with divided doses of steroids strongly decreases side effects of OKT3. Kidney Int 1994;46:1674-9.

Parlevliet KJ, ten Berge IJ, Yong SL, Surachno J, Wilmink JM, Schellekens PT. In vivo effects of IgA and IgG2a anti-CD3 isotype switch variants. J Clin Invest1994;93:2519-25.

Raasveld MH, Surachno S, Hack CE, ten Berge RJ. Thromboembolic complications and dose of monoclonal OKT3 antibody. Lancet 1992;339:1363-4.

Van Twuyver E, Mooijaart RJ, ten Berge IJ, van der Horst AR, Wilmink JM, Kast WM, Melief CJ, de Waal LP. Pretransplantation blood transfusion revisited. N Engl J Med 1991;325:1210-3.

Contact

For further information about our research and opportunities for work or collaborations, you can contact Prof. Ineke ten Berge

+31 (0)20 566 5990

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