Abstract: Up to one third of candidates for organ or hematopoietic stem cell transplantation in the United States have antibodies to histocompatibility antigens, the most problematic of which are those of the HLA genetic system. The presence of high levels of HLA-specific antibodies reduces access to transplantation as a treatment option for many patients, and, for others with lower levels, increases the risk of rejection and impacts long term graft survival. Other polymorphic antigens, as well as some autologous antigens, have also been implicated in antibody mediated rejection and may act in concert or synergy with HLA-specific antibodies. The degree of risk imposed by antibodies correlates with their level or strength, with low levels evoking less damage and under some circumstances perhaps even offering some protective benefit. Clinical protocols now provide options for overcoming or circumventing humoral sensitization while research on the signaling pathways triggered by antibodies binding to their target antigens may lead to improved options for therapeutic intervention.
The first solid organ and bone marrow transplants were performed more than fifty years ago and in the ensuing years, transplantation has become commonplace as a preferred and life-saving treatment for end stage organ failure, hematologic malignancies, and certain congenital immunodeficiencies. For much of this history, the presence of antibodies to the major histocompatibility antigens, those of the HLA (commonly referred to as human leukocyte antigen) system, posed a barrier to transplantation (Zachary and Leffell, 2010). The definitive test for compatibility was a crossmatch of recipient serum against donor lymphocytes in a complement dependent cytotoxicity (CDC) assay. When antibodies were present at levels sufficient to render a positive crossmatch, they generally were considered as an absolute contraindication to transplantation in solid organ transplantation. Until recently, HLA-specific antibodies were not usually taken into consideration in bone marrow or hematopoietic stem cell transplantation (HSCT) since transplants usually were performed with donors HLA identical to their recipients. Today, however, donors with some degree of HLA mismatch are being used in HSCT to extend the option of transplantation to patients lacking an HLA identical donor.
Characterization of the precise specificity of anti-allograft reactive antibodies was hampered by the relatively insensitive and non-specific method of detection: a serologic crossmatch test of recipient serum against donor cells in assays that could detect antibodies not only to HLA, but also to numerous tissue specific and autologous antigens. During the past fifteen years, the development of sensitive solid phase immunoassays (SPA) using purified, soluble antigens has greatly advanced the understanding of the role of HLA and other specific antibodies in the immune response to allografts. We review here briefly the different types of antigens that provoke allograft reactive antibodies, methods and issues with their detection, and treatments that can overcome their impact on transplant outcomes.
Characteristics of Anti-allograft Antibodies and Their Impact on Transplant Outcomes
Aside from the ABO isohemagglutinins which can be circumvented by performing ABO compatible transplants, antibodies to HLA antigens confer the greatest risk to allografts. Antibody mediated rejection (AMR) caused by HLA-specific antibodies adversely impacts graft survival of renal, pancreas, heart, and lung transplants (Leffell and Zachary, 2010). The impact of antibodies on liver allografts has been unclear, although the presence of HLA-specific antibodies before transplantation recently has been shown to be associated with a significant decrease in graft survival (Castillo-Rama et al., 2008). The antibody level or titer clearly correlates with the amount of risk to the allograft. Pre-existing, high levels of HLA-specific antibodies detectable by CDC crossmatches can result in hyperacute rejection of renal grafts. Memory, or anamnestic, antibody increases in individuals sensitized to HLA may occur early or late after transplantation and may be substantial, evoking a severe AMR that is difficult to treat. When HLA-specific antibodies develop de novo during the first post-transplant year, they are associated with an increased incidence of chronic rejection (Lee et al., 2009). The appearance or persistence of low levels of antibodies correlates with the arteriosclerosis, tissue ischemia, and interstitial fibrosis associated with transplant vasculopathy and chronic rejection (Singh et al., 2009; Kwum and Knechtle, 2009). The majority of late kidney allograft loss is attributable to antibody mediated microcirculation injury evidenced by inflammation and scarring, often without any evidence of complement involvement by C4d deposition and consistent with repeated, subclinical antibody attacks (Einecke et al., 2009).
Antibodies to the HLA-A, -B, -DRB1, and -DQB1 encoded antigens have been most often implicated in AMR, but with the improved detection afforded by SPA, it has been shown that humoral sensitization occurs to other HLA molecules, as well as to HLA related gene products (Leffell and Zachary, 2010). A recent study has shown that the rate of sensitization to HLA-C antigens, which are expressed at lower levels than other class I HLA molecules, is less frequent than to HLA-A or -B antigens, but still occurs in 42% of sensitized patients (Bryan et al., 2009). In addition to the deleterious effects of antibodies to the beta chain of HLA-DQ molecules, antibodies to the HLA-DQ alpha chain have also been reported to result in renal graft rejection (Zeevi et al., 2009). Similarly, antibodies reactive with HLA-DP have been associated with both acute and chronic humoral rejection (Thaunat et al., 2009; Samaniego et al., 2006). To date only antibodies to the HLA-DP beta chain have been reported, but HLA-DP specific antibodies appear to be directed against epitopes shared among different HLA-DP antigens and some HLA-DR antigens (Billen et al., 2010).
The major histocompatibility complex (MHC) class I related genes A and B (MICA and MICB) products are also polymorphic and can stimulate alloimmune responses. Both MICA and MICB can be stress-induced on endothelial cells and antibodies to these antigens have been implicated in renal graft loss in recipients who were otherwise well matched for HLA (Stastny et al., 2009; Terasaki et al., 2007). Antibodies to MICA have been eluted from rejected renal allografts, which supports a causal relationship between these antibodies and graft loss (Zou et al., 2006). MICA specific antibodies have also been associated with the development of cardiac allograft vasculopathy and acute cellular rejection (Kauke et al., 2009). In contrast, Smith et al. (2009) found superior 1- and 5-year graft survival among their heart recipients with MICA specific antibodies compared to that among other patients without these antibodies — 89 and 83% compared to 72 and 64%, respectively. Among lung transplant recipients, the development of HLA-specific antibodies has been shown to precede that of anti-MICA antibodies. Antibodies to both were strongly associated with bronchiolitis obliterans syndrome or chronic rejection in the lung (Angaswamy et al., 2010). Therefore, in renal and lung transplantations, the frequent co-existence of MICA- and HLA-specific antibodies suggests that these antibodies may act synergistically to mediate allograft injury.
Vascular endothelium is the primary interface between circulating antibodies and an allograft. Therefore, antigens expressed on endothelial cells have been the focus of recent studies. In addition to MICA, there are several, non-polymorphic auto-antigens that have been implicated as possible endothelial cell targets, including the angiotensin II type 1 receptor, intracellular adhesion molecule-1, vimentin, actin, tubulin, and cytokeratin (Sumitran-Holgersson, 2008; Dragun, 2008; Alvarez-Marquez et al., 2008). A significantly higher incidence of rejection was demonstrated for patients with endothelial cell reactive antibodies in a multi-center trial using a crossmatch test against endothelial cell precursors isolated from peripheral blood (Breimer et al., 2009). Among the renal transplant recipients with positive crossmatches, the incidence of rejection was higher in the first two weeks post-transplant (37 versus 5%), as well as through the first three months post-transplant (46 versus 12%), compared to patients with negative crossmatches. There may, in fact, be a causal relationship between some of these endothelial reactive, auto-reactive, and HLA-specific antibodies. There is evidence that antibodies to HLA may induce the formation of auto-antibodies that contribute to chronic rejection in heart, lung, and kidney transplantation. Passive transfer of anti-MHC antibodies in a murine model provokes the formation of antibodies to cytoskeletal components and results in a pathology consistent with chronic rejection (Tiriveedhi et al., 2010). It should be noted that, in the absence of HLA-specific antibodies, IgM auto-antibodies are generally not considered a contraindication to transplantation. However, elucidation of the nature and types of endothelial cell antigens and the relationship of HLA and endothelial cell reactive antibodies remains an exciting area for further research.
Methods of Detection: Advantages, Limitations, and “Virtual” Crossmatches
As noted earlier, current definition of the various antigens that can induce allograft reactive antibodies has been greatly facilitated by the development of SPA. They have greatly increased sensitivity and specificity compared to cell based methods; however, SPA are not without some problems and limitations. The sensitivity and specificity of the assays for HLA-specific antibodies results from the use of purified, soluble HLA antigens adsorbed onto various matrices, including microtiter plates, polystyrene microbeads, and glass chips. The HLA targets are applied in three formats: antigens pooled from multiple individuals, panels of class I or class II phenotypes from single individuals, or panels of single HLA molecules. Specific binding is detected by immunofluorescence or enzyme-linked assays using antiglobulin reagents conjugated with fluorochromes or enzymes. The sensitivity of these SPA ranges in increasing order: pooled antigens, phenotypes, single antigens (Zachary and Leffell, 2008). The exquisite sensitivity of SPA, particularly of the single antigen assays, permits detection of antibodies at a level of unknown clinical relevance (discussed further below). At present it is incumbent upon individual histocompatibility laboratories to correlate SPA results with their acceptance criteria for transplants, generally either flow cytometric or CDC crossmatch results. In our experience, much better correlation was observed with phenotype than with the single antigen assays (Zachary et al., 2009b). This observation likely results from two factors: first, that phenotype assays provide targets more closely approaching the state of nature, i.e., inclusion of multiple antigens as targets for the diverse antibodies present in polyclonal sera; second, that the concentrations of single antigens vary considerably, from antigen to antigen and from lot to lot. The sensitivity of SPA also renders them susceptible to daily variation and to interference from immune complexes and high levels of IgM antibodies that can block specific binding (Zachary et al., 2009a). Such interference, if not recognized, can lead to misinterpretations, potentially even failure to identify clinically significant antibodies.
There is currently great interest in the opportunity to perform “virtual crossmatches” capitalizing on the specificity of SPA to define HLA-specific antibodies. This application facilitates placement of deceased donor organs by eliminating needless shipment of organs to potential recipients who are later found to be crossmatch positive (i.e., presence of donor specific antibody). Prediction of negative crossmatches is readily achieved with SPA due to their sensitivity. Positive crossmatch predictions, while more difficult, have also been demonstrated with high degrees of accuracy, when antibody strength is taken into consideration. We have shown that both the identity and strength of donor specific antibody correlate significantly with the CDC and flow cytometric crossmatches, r=0.83 and 0.85, respectively. Based on thresholds established from these correlations, crossmatches evaluated by CDC and flow cytometry were predictable with 92.8 and 92.4% respective accuracy (Zachary et al., 2009b). In another approach of controlling assay variability in single antigen SPA by normalization to positive controls, 98.5% and 93.1% positive predictions were achieved with CDC and flow cytometric crossmatches, respectively (Morris et al., 2010). Importantly, application of the virtual crossmatch has increased access to transplantation for highly sensitized patients (Bingaman et al., 2008; Reinsmoen et al., 2008).
HLA-Specific Antibodies: What levels are relevant?
Given the high sensitivity of SPA, recent studies have addressed the question of how much antibody is clinically relevant by correlating the presence of pre-transplant donor HLA-specific antibody with the incidence of acute, post transplant AMR. While there is not yet a consensus, there is a correlation with antibody level or relative strength. Antibodies detectable only by the more sensitive SPA on Luminex® or flow cytometric platforms do not appear to adversely impact allograft outcomes in the short term (Lefaucheur et al., 2008; Aubert et al., 2009). In contrast, antibodies detectable by ELISA, which in the authors’ experience correlate with positive flow cytometric crossmatches, are associated with an increased AMR incidence (Zachary and Leffell, 2010; Morris et al., 2009). A multicenter study among 1,134 renal recipients examined the impact of pre-transplant antibodies detectable by ELISA (Susal et al., 2009). Although the study was limited by the lack of definition of donor specific antibodies, a significant increase in early rejection episodes was observed among the patients with HLA class I specific antibodies (OR=2.53, p<0.001). While antibodies detectable only by the more sensitive SPA do not appear to result in an increased incidence of acute AMR, there is growing evidence that low level antibodies, either present prior to or developing de novo after transplant, can evoke sub-clinical AMR that ultimately contributes to the pathology of chronic rejection (Loupy et al., 2009; Lee et al.,2009). Studies of renal allograft recipients indicate that antibodies specific for HLA class II antigens are most commonly associated with the development of transplant glomerulopathy (Colvin, 2009).
Recent work is delineating the molecular basis for the impact of different levels of anti-allograft antibodies. Reed and colleagues have demonstrated in a series of studies that antibodies can contribute to graft dysfunction via complement-independent mechanisms affecting endothelial cell signal transduction (Zhang and Reed, 2009). Low titer antibodies appear to stimulate both cell survival and proliferation through pathways leading to the concomitant activation of mTORC1 and mTORC2 (mammalian target of rapamycin complexes 1 and 2). Chronic changes resulting from these activation pathways likely contribute to transplant vasculopathy. Other studies suggest that low levels of antibody can be protective against complement mediated injury. HLA ligation on endothelial cells at low antibody concentrations induces PI3K/AKT signal pathways followed by antioxidant gene induction, providing enhanced protection from complement-mediated damage (Iwasaki, 2010). Thus, while high levels of anti-allograft antibody can clearly evoke acute AMR, the impact of lower antibody levels may vary with time, in acute stages affording some protective benefit, but with time, contributing to chronic rejection.
In addition to their deleterious effects, low levels of antibody could contribute to the phenomenon of allograft “accommodation.” Accommodation is defined as good graft function without rejection in the face of circulating donor reactive antibodies (Lynch and Platt, 2008). This phenomenon is most often observed with ABO blood group incompatible transplants, but may also occur with HLA antibody incompatible transplants. Various mechanisms have been suggested to contribute to accommodation, including the up-regulation of the survival genes, Bcl-2 and Bcl-x; changes in antigen expression; and/or antibody isotype switching. Another model involves antibody induced expression of complement regulatory molecules, such as DAF and CD59, on endothelial cell membranes. Numerous important questions remain that will benefit from further research on the molecular consequences of anti-allograft antibodies — the one, perhaps, most pressing being whether or not there is a threshold level determining whether antibodies are damaging or perhaps beneficial.
Overcoming Anti-allograft antibodies
Anti-allograft antibodies present an impediment to transplantation for more than 35% of the candidates waiting for solid organ transplants. Currently more than a quarter of renal transplant candidates are very highly sensitized with antibodies reactive to 80% or more of potential donors (U.S. DHHS, 2008 OPTN/SRTR Data). Sensitization is also a growing problem for HSCT candidates involving HLA mismatches. At best only 30% of HSCT patients have a suitable related HLA identical donor; therefore, transplants between recipient and donors with some degree of HLA mismatch are increasing in frequency. The rate of sensitization among HSCT candidates resulting from pregnancy and/or transfusion can approach that of solid organ candidates. For example, the rate of sensitization among HSCT patients at the authors’ center for the past three years has been 28.7% (unpublished data). Given the magnitude of pre-existing sensitization among transplant candidates, it is not surprising that there is great interest in finding ways to overcome anti-allograft antibodies.
Prevention and treatment of AMR has been dominated, historically, by the development of stringent immunosuppression regimens that often increased the rates of infection and malignancy. It is, therefore, highly desirable to either eliminate sensitization to HLA or to somehow circumvent it. A program which identifies “acceptable HLA mismatches” has been successful in achieving transplantation of sensitized patients in Eurotransplant. This system relies on identification of HLA epitopes to which a patient has not made antibody, an HLA-DR matching requirement, and mandatory sharing of deceased donors matched by these criteria (Claas et al., 2004). Unfortunately, limited sharing of deceased donor organs limits the practicality of this approach for patients in the U.S. However, a national pilot program of paired kidney donation is being initiated in an effort to extend the pool of potentially compatible donors for candidates who have a willing, but incompatible, living donor (Sokohl, 2010). The goal of the program is to arrange the exchange of donors among sensitized candidates to achieve a number of compatible donor:recipient pairs. Paired donation has been shown to be successful in transplanting highly sensitized patients, particularly when it can be initiated by an altruistic donor or extended through donor chains (Montgomery, 2010; Rees et al., 2009).
An alternative to avoiding pre-existing sensitization is to down-regulate or reduce antibodies to a level that is safe for transplantation. Two desensitization protocols have achieved such results with the use of intravenous immunoglobulin (IVIg). One approach uses multiple treatments with high dose of IVIg (2gm/kg) combined with rituximab, while the other employs a lower dose of IVIg (100mg/kg) combined with alternate day plasmapheresis. Both approaches have been shown to reduce HLA-specific antibodies permitting successful transplantation and can also be used in the treatment of acute episodes of AMR (Warren and Montgomery, 2010; Vo et al., 2009; Zachary et al., 2003). Desensitization can be applied simultaneously to HLA specific antibodies and ABO isohemmaglutinins and also can be coupled with paired donation to further increase the number of possible donor:recipient pairs in cases where a recipient who has very high levels of antibody to their original, intended donor may have much lower antibody levels, amenable to desensitization, to an exchange donor (Warren et al., 2004; Montgomery, 2010). Pharmacological approaches aimed at reducing HLA-specific antibodies selectively target B lymphocytes and plasma cells. Rituximab, a chimeric monoclonal antibody against CD20, effectively depletes circulating B lymphocytes and has been used singly or in combination with other drugs and/or desensitization (Zarkhin et al., 2008). More recently, bortezomib, a reversible inhibitor of the 26S proteasome, has been shown to induce apoptosis of plasma cells with subsequent reductions in alloantibody levels (Perry et al., 2009; Everly et al., 2009).
While there has undoubtedly been significant progress in the definition of both HLA and non-HLA-specificities of allograft reactive antibodies, as well as substantial advances in the treatment options for AMR, alloantibodies remain a substantial barrier to transplantation for many patients. Highly sensitive SPA have clearly demonstrated that low levels of antibody can persist without overt signs of clinical rejection, but which, overtime, may contribute to chronic rejection. Continued efforts will certainly be focused on improved treatment options, but real progress toward overcoming humoral sensitization will likely also come from better understanding of the factors that determine when antibodies are tolerated or “accommodated” versus when they become pathogenic.
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[Discovery Medicine, 9(48):478-484, May 2010.]