Clinical and Experimental Immunology



7th International Immunoglobulin Conference: Transplantation

S. C. Jordan* and D. Glotz† *Cedars-Sinai Medical Center, Los Angeles, CA, USA, and †Department of Nephrology and Renal Transplantation, Saint-Louis Hospital, Paris, France

Correspondence: S. C. Jordan. E-mail: [email protected]

Summary In transplantation, harnessing the immune system is essential for allograft survival and function. This session explores different aspects of the immune system during transplantation, including the effect of donor-specific antihuman leucocyte antigen (HLA) antibodies (DSAs), antibody-mediated rejection (AMR), B cell modulation and the role of immunoglobulin (Ig) therapy. It is well known that DSAs play a key role in the failure of allografts. Identifying and characterizing DSAs provides information that can aid in risk stratification of transplant recipients. The ability to bind complement provides additional information regarding the cytotoxic potential of these antibodies and can therefore potentially guide individualized treatment strategies. AMR presents as several phenotypes, which vary in severity. As such, potentially different treatment strategies are required, emphasizing the importance of accurate diagnosis. In patients with elevated anti-HLA antibodies, waiting times for a compatible organ are often prolonged. Desensitization protocols using intravenous immunoglobulin (IVIg), in combination with other therapies, have been developed to enhance the availability of compatible donors. Another important aspect of transplantation is the role of B cells. While B cells may be involved in AMR and forms of cellular rejection, there is evidence to suggest that regulatory B cells may also have a positive impact upon long-term graft survival. Hypogammaglobulinaemia (HGG) has been reported after solid organ transplantation and is associated with an increased risk of infections. Monitoring immunoglobulin G (IgG) levels post-transplantation may identify patients at risk for infections who could potentially benefit from pre-emptive treatment with IVIg. Keywords: antibody-mediated rejection, B cell modulation, desensitization, donor-specific anti-HLA antibodies, immunoglobulin

Introduction Allograft rejection has always been the chief obstacle to transplantation success. Advances in the field of transplantation have highlighted the harmful effects of donorspecific anti-human leucocyte antigen (HLA) antibodies (DSAs) on allografts, and that chronic graft loss is part of the antibody-mediated rejection (AMR) spectrum. In this paper, a variety of important factors in transplantation are discussed, particularly immune-related features that can be detected or modified to identify high-risk patients and improve allograft survival. Potential applications of intravenous immunoglobulin (IVIg) are also presented. 46

DSAs are known to promote various types of AMR. A variety of assays are available for the identification and characterization of HLA antibodies. Dr Zeevi discusses new diagnostic tools, including the C1q-DSA assay, which detects antibodies that are capable of binding and fixing the first complement protein, C1q [1–3], and can therefore aid in risk stratification of transplant recipients who exhibit DSA. Early detection of DSA and intervention strategies may impact long-term allograft survival. Dr Lefaucheur presents the results of a population-based study of kidneytransplant recipients who were screened for the presence of circulating DSA at the time of transplantation and at 1 year after transplantation. A risk prediction model that

© 2014 British Society for Immunology, Clinical and Experimental Immunology, 178: 46–47

Ig use in transplantation

incorporates the ability of DSA to bind complement demonstrates an improved risk stratification process which aids identification of patients at high risk of graft loss, leading potentially to specific and personalized treatment options. The deleterious effects of antibodies to HLA antigens are well known and prohibitive to transplantation. For example, patients with elevated anti-HLA antibodies often wait for extended periods for a compatible organ [4]. Desensitization protocols using IVIg in combination with plasma exchange and/or rituximab have been developed to optimize the availability of compatible donors [5,6]. Dr Vo discusses data regarding the safety, efficacy and economic aspects of the current desensitization protocols. Professor Legendre discusses AMR in more detail, and highlights that various phenotypes of acute AMR exist, including subclinical AMR [7], C4d-negative AMR [8], AMR with vascular lesions [9] and AMR without anti-HLA antibodies but with DSA of other origin [10,11]. These phenotypes vary in severity and potentially require different treatments, highlighting that accurate diagnosis is essential for effective treatment strategies. In contrast to the role of DSAs and AMR in allograft survival, Dr Clatworthy discusses the various effects of B cells. There is an appreciation that B cells may play a function in acute cellular rejection and are probably important in rebound AMR after incompatible kidney transplantation. However, aside from the negative effects of B cells and antibody on the allograft, evidence suggests that B cells may have a favourable effect on long-term graft survival, due possibly to the effect of ‘regulatory’ B cells [12–14]. Possible strategies to target B cells are presented. Hypogammaglobulinaemia (HGG) is a known complication of solid organ transplantation and is associated with an increased risk of infection. Monitoring serum immunoglobulin G (IgG) levels before and after transplantation has been proposed as a tool to predict clinical outcomes. Dr Florescu presents the results of a meta-analysis that was performed to evaluate the risk of HGG and its impact on the rate of opportunistic infections during the first year posttransplantation [15]. The results demonstrate that HGG is associated with an increased risk of infection and has a negative impact on mortality. No impact of HGG on the rate of transplant rejection was observed. The impact of treatment of HGG with IVIg was also presented.

Acknowledgements The authors would like to thank Meridian HealthComms Ltd for providing medical writing services.

Disclosures S. C. J. has received consultation and grant support from CSL Behring and Genentech-Roche. D. G. has received

support for consulting, conferences and/or research from CSL Behring, One Lambda, Astellas and ROTRF.

References 1 Tait BD, Susal C, Gebel HM et al. Consensus guidelines on the testing and clinical management issues associated with HLA and non-HLA antibodies in transplantation. Transplantation 2013; 95:19–47. 2 Chin C, Chen G, Sequeria F et al. Clinical usefulness of a novel C1q assay to detect immunoglobulin G antibodies capable of fixing complement in sensitized pediatric heart transplant patients. J Heart Lung Transplant 2011; 30:158–63. 3 Yabu JM, Higgins JP, Chen G, Sequeira F, Busque S, Tyan DB. C1q-fixing human leukocyte antigen antibodies are specific for predicting transplant glomerulopathy and late graft failure after kidney transplantation. Transplantation 2011; 91:342–7. 4 Jeannet M, Pinn VW, Flax MH, Winn HJ, Russell PS. Humoral antibodies in renal allotransplantation in man. N Engl J Med 1970; 282:111–7. 5 Montgomery RA, Lonze BE, King KE et al. Desensitization in HLA-incompatible kidney recipients and survival. N Engl J Med 2011; 365:318–26. 6 Vo AA, Petrozzino J, Yeung K et al. Efficacy, outcomes, and costeffectiveness of desensitization using IVIG and rituximab. Transplantation 2013; 95:852–8. 7 Loupy A, Suberbielle-Boissel C, Hill GS et al. Outcome of subclinical antibody-mediated rejection in kidney transplant recipients with preformed donor-specific antibodies. Am J Transplant 2009; 9:2561–70. 8 Solez K, Colvin RB, Racusen LC et al. Banff 07 classification of renal allograft pathology: updates and future directions. Am J Transplant 2008; 8:753–60. 9 Lefaucheur C, Loupy A, Vernerey D et al. Antibody-mediated vascular rejection of kidney allografts: a population-based study. Lancet 2013; 381:313–9. 10 Aubert O, Bories MC, Suberbielle C et al. Risk of antibodymediated rejection in kidney transplant recipients with antiHLA-C donor-specific antibodies. Am J Transplant 2014; 14:1439– 45. 11 Sicard A, Amrouche L, Suberbielle C et al. Outcome of kidney transplantations performed with preformed donor-specific antibodies of unknown etiology. Am J Transplant 2014; 14:193– 201. 12 Newell KA, Asare A, Kirk AD et al. Identification of a B cell signature associated with renal transplant tolerance in humans. J Clin Invest 2010; 120:1836–47. 13 Pallier A, Hillion S, Danger R et al. Patients with drug-free longterm graft function display increased numbers of peripheral B cells with a memory and inhibitory phenotype. Kidney Int 2010; 78:503–13. 14 Viklicky O, Krystufkova E, Brabcova I et al. B-cellrelated biomarkers of tolerance are up-regulated in rejectionfree kidney transplant recipients. Transplantation 2013; 95: 148–54. 15 Florescu DF, Kalil AC, Qiu F, Schmidt CM, Sandkovsky U. What is the impact of hypogammaglobulinemia on the rate of infections and survival in solid organ transplantation? A meta-analysis. Am J Transplant 2013; 13:2601–10.

© 2014 British Society for Immunology, Clinical and Experimental Immunology, 178: 46–47


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7th International Immunoglobulin Conference: Transplantation.

In transplantation, harnessing the immune system is essential for allograft survival and function. This session explores different aspects of the immu...
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