Abstract
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 anti-human 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 donor-specific 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.
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 kidney-transplant 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 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 post-transplantation 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.
Acknowledgments
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.
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