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Venkataswarup Tiriveedhi

Cross-talk of Alloimmune Response and Autoimmunity: Role in Pathogenesis of Chronic Rejection

Abstract: Chronic rejection following organ transplantation continues to be a major problem in the long-term survival of the engraftment. Recent literature points to role of both the humoral and cellular alloimmune responses in the pathogenesis of chronic rejection. Our recent studies have provided evidence for alloimmune-response-induced de novo development of immune responses to self-antigens in the post-transplant period in the pathogenesis of chronic rejection following lung, heart, and kidney transplantation. This review details our current understanding of two distinct yet inter-dependent immune processes in the immunopathogenesis of chronic rejection.



Introduction

Solid organ transplantation in the form of a vascularized allograft is the treatment of choice for patients with end-stage organ dysfunction. The demand for solid organ donation still vastly exceeds the number of suitable donors. Recent statistics from Scientific Registry of Transplant Recipients 2008 shows a waiting list of 97,400 patients, while there were just 27,961 organ transplantations performed in 2008 (Stevens et al., 2008). These facts underline the importance of delineating the immunopathogenesis of rejection to enhance the long-term graft survival following solid organ transplantation.

Transplant rejection still remains a major challenge. Rejection of the transplanted organ can occur in 3 major pathways: hyperacute, acute, and chronic (Griffith et al., 1988; Viklicky et al., 2010). While significant improvement in donor recipient matching, post-operative care, and therapeutic strategy has led to decrease in the hyperacute and acute rejection of the graft, there has been much less progress in addressing the effects of chronic rejection. Due to its complicated immunopathogenesis, chronic rejection still remains the leading cause of long-term allograft failure in transplant recipients. Several risk factors have been proposed to play a role in chronic rejection. They include recurrent/refractory acute rejections, cytomegalovirus (CMV) and other viral infections, human leukocyte antigen (HLA) mismatches, organ ischemia, etc. (Kroshus et al., 1997; Stanbrook and Kesten, 1999). Several non-specific risk factors such as donor and recipient age, graft ischemic time, and bacterial/fungal/non-CMV viral infection have also been associated with decreased long-term survival of the graft (Kshettry et al., 1996; Stanbrook and Kesten, 1999; Tilney, 1999). We propose that all the above mentioned risk factors cause inflammation and tissue remodeling which facilitates the induction of autoimmune responses against self-antigens leading to chronic rejection. In this review, we will discuss our hypothesis towards the role of alloimmune mechanisms leading to the development of autoimmunity resulting in the pathogenesis of chronic rejection.

Chronic Rejection

The hallmark of chronic rejection is fibrosis of graft parenchyma developing over months to years. The pathogenesis of chronic rejection is initiated by a host-anti-graft-immune response. Both immune (antigen-dependent) and non-immune (antigen-independent) factors lead to fibroproliferative changes that cause occlusion of tubular structures in the allograft (Nath et al., 2010). This is characterized by terminal airway obliteration in lung allografts, focal cellular interstitial infiltration and glomerulosclerosis in renal allografts, and coronary arteriopathy in cardiac allografts.

Recent studies have shown that the allorecognition of mismatched donor HLA antigens as the critical event that initiates chronic rejection. Donor antigen recognition can occur either by direct and indirect pathways (Game and Lechler, 2002) and recent lines of evidence have shown that indirect antigen presentation as the major player involved in the pathogenesis of chronic rejection (Benichou et al., 1999; Heeger, 2003). The indirect pathway involves presentation of processed donor antigens by recipient antigen presenting cells (APCs) to recipient T cells triggering an alloimmune response including production of donor specific antibodies (Heeger, 2003).

Alloantibodies in Chronic Rejection

Suciu-Foca et al. demonstrated that de novo development of anti-HLA antibodies (Abs) following heart and renal transplantation correlates with the development of chronic rejection (Cherry et al., 1992; Jindra et al., 2008; Suciu-Foca et al., 1991; Suciu-Foca et al., 1991). They postulated that chronic rejection is mediated by T helper cells recognizing processed forms of soluble HLA in the context of self-MHC (major histocompatibility complex) and these T cells are likely involved in the development of Abs to donor HLA. The presence of circulating cytotoxic anti-HLA Abs have been strongly associated with chronic allograft rejection of heart and renal transplants (Ciancio et al., 2005; Jindra et al., 2008).

Studies (Jaramillo et al., 1999; Rose and Smith, 2009) demonstrated that development of anti-HLA class I Abs is associated with the development of chronic rejection, clinically diagnosed as Broncholitis Obliterans Syndrome (BOS) after human lung transplantation (LTx). Based on the reports by us (Rizzo et al., 1997) and others (DeVito-Haynes et al., 1997) on the presence of ’shed’ donor HLA antigens in the bronchoalveolar lavage fluids following LTx, it has been proposed that these donor HLA antigens are processed and presented to T helper cells. Such T helper cells, which are engaged in indirect recognition pathways, can produce lymphokines required for the growth and maturation of alloantibody producing B cells. Studies from our laboratories have also demonstrated that anti-HLA Abs can activate human airway epithelial cells (AEC) resulting in the production of several growth factors including fibrinogenic growth factors (Goers et al., 2008) which can play an important role in the pathogenesis of chronic rejection (Jaramillo et al., 1999; Reznik et al., 2001). Yamakuchi et al. (2007) have shown that ligation of HLA molecules on endothelial cells by anti-HLA Abs can result in exocytosis of Weibel-Palade bodies, and up-regulation of PI3k/Akt signaling pathway that leads to growth factor production and release (Jin et al., 2004; Li et al., 2009).

Chronic rejection of cardiac allografts is manifested by cardiac allograft vasculopathy (CAV), which is characterized by occlusion of coronary vessels. The 5-year incidence of CAV is 30-40%, and the development of donor-specific HLA Abs has been correlated with chronic rejection (Kaczmarek et al., 2008). Chronic rejection termed chronic allograft nephropathy (CAN) is the leading cause of renal function deterioration and accounts for nearly 40% of the graft loss at 10 years (Hertig et al., 2008). Increased levels of pre-transplant anti-HLA Abs and de novo post-transplant donor specific Abs, as well as CD4+ alloreactive T cells responding to donor derived peptides have all been correlated with CAN (Birnbaum et al., 2009). However, Abs developed de novo and directed at the donor HLA are not always detectable in the circulation of patients undergoing chronic rejection, questioning the significance of Abs to HLA in the pathogenesis of chronic rejection.

Development of Autoantibodies in Chronic Rejection

Several recent studies strongly suggest an important role for autoimmunity in the pathogenesis of allograft rejection (Bharat et al., 2006; Milne et al., 1992; Shulman and Sullivan, 1988). Our studies in LTx recipients have shown a strong correlation between the development of Abs to a self protein, K-α1 tubulin (K-α1T), and the development of BOS following human LTx. Reports by Wilkes and Burlingham and other groups have also provided compelling evidence for autoimmunity to collagen V (ColV), a sequestrated yet immunologic self protein present in the lung tissue, for the development of chronic lung allograft rejection (Benichou et al., 1999; Burlingham et al., 2007; Haque et al., 2002; Iwata et al., 2008; Mizobuchi et al., 2003; Sumpter and Wilkes, 2004). Tissue remodeling following transplantation can expose cryptic self antigens or their determinants that can trigger an immune response. Furthermore, lung allografts are uniquely susceptible to injuries from a variety of both endogenous and exogenous agents due to their direct communication with the environment, resulting in increased inflammation and tissue repair. Therefore, the findings by Wilkes and Burlingham and their colleagues that autoimmunity to ColV plays an important role in the pathogenesis of chronic lung allograft rejection is highly significant (Burlingham et al., 2007; Haque et al., 2002). Studies have also shown ColV reactive T cells in rat lung allograft undergoing rejection (Haque et al., 2002). More important is that ColV specific T cells derived from rat lung allografts can cause rejection of isografts when adoptively transferred without affecting native lung (Haque et al., 2002). Our studies have shown high frequency of ColV reactive T cells in human lung allograft recipients (Bharat et al., 2006) and BOS was associated with expansion of IFN-γ producing ColV specific Th-1 cells with a concomitant reduction in IL-10 secreting T cells (Bharat et al., 2006).

As mentioned earlier, a proportion of the transplant recipients undergo chronic rejection despite the absence of any detectable anti-HLA Abs (Grossman and Shilling, 2009; Hachem, 2009). In many such cases, Abs against non-HLA antigens have been implicated in the development of chronic rejection. Studies with sera from LTx recipients with BOS, where there were no demonstrable Abs to donor HLA, lead us to identify Abs against self-antigens, K-α1T, an airway epithelial surface antigen (Goers et al., 2008) and Col-V, an extracellular matrix protein (Iwata et al., 2008). Also of significant is our finding that about 50% of BOS+ patients with detectable anti-HLA Abs also developed Abs against K-α1T. The development of Abs to both donor HLA as well as to K-α1T preceded the clinical diagnosis of BOS. In addition, we demonstrated that binding of anti-K-α1T to AEC activates a PKC-driven calcium maintenance pathway that is regulated by heat shock proteins (HSP) 27 (HSP27) and 90 (HSP90), culminating in increased growth factor production, cellular mitosis, and proliferation (Goers et al., 2008). Exposure of AECs to sera from BOS+ LTx recipients also resulted in an up-regulation in transcription factors TCF5 and c-Myc and proliferation factors HB-EGF, TGF-β, and VEGF. Collectively, these results strongly suggest that binding of anti-K-α1T Abs to AECs results in up-regulation of proinflammatory response genes and activation of fibroproliferation cascade. Higher frequency of T cells specific for K-α1T as well as ColV have been noted in LTx undergoing chronic rejection (Fukami et al., 2009; Hachem, 2009). A longitudinal study in LTx patients also demonstrated an association between ColV specific IL-17 responses with onset of BOS (Burlingham et al., 2007). ColV-specific responses in BOS patients were found to be dependent on both CD4+ T cells and monocytes and required IL-17, TNF-α, and IL-1β. Furthermore, adoptive transfer of lymph node cells expressing high levels of IL-17 and IL-23 gene transcripts from ColV-sensitized mice have been shown to induce obliterative lesions in the lung isograft. These results clearly demonstrate that cell-mediated immunity to self-antigens can also lead to chronic rejection in the absence of alloantigen.

Experiments using syngeneic heart transplants provided initial evidence that chronic rejection can be induced even in the absence of an alloimmune response (Atz and Reed, 2008; Jindra et al., 2008). T-cell-mediated autoreactivity against cardiac myosin has been shown to develop and persist in the absence of an alloimmune response, indicating that response to myosin, a self antigen, is associated with the pathogenesis of CAV (Kaczmarek et al., 2008; Rose and Smith, 2009). Additionally, pre-transplant sensitization with cardiac myosin can result in accelerated rejection of both allo- and syngeneic cardiac grafts (Rose and Smith, 2009). Studies have also indicated that Abs against vimentin, a cytoskeleton protein, are an independent predictor of coronary atherosclerosis following cardiac transplantation and may contribute to the accelerated onset of transplant associated coronary vasculopathy (Leong et al., 2008; Rose and Smith, 2009).

In kidney allografts, transplant glomerulopathy has an incidence of 20% by the 5th year post-transplant (Fotheringham et al., 2009). A recent multi-center trial involving refractory vascular allograft rejection in the absence of detectable anti-HLA Abs demonstrated the presence of Abs directed at two epitopes of the second extracellular loop of the angiotensin II type 1 (AT1) receptor. Furthermore, it has been suggested that detection of anti-AT1 receptor might be a useful tool to identify those at risk for refractory allograft rejection (Fotheringham et al., 2009; Li and Yang, 2009).

Are the Autoantibodies Passive Player or Are They Actively Involved in the Pathogenesis of Chronic Rejection?

Abs against MHC class I antigens developed following transplantation increase risk for both early allograft failure and development of chronic rejection following transplantation (Hachem, 2009; Shilling and Wilkes, 2009). We and others previously demonstrated that the development of anti-MHC class I Abs precedes the development of BOS by 20 months (Jaramillo et al., 1999). As discussed above, these patients also developed Abs to self antigens prior to clinical onset of BOS. Therefore, to determine the mechanism by which Abs to donor MHC may induce an immune response to self antigen which leads to chronic rejection, we developed a murine model of OAD of native lungs. In this model, administration of specific anti-MHC class I Abs to the native lungs of mice resulted in autoimmunity leading to cellular infiltration, epithelial hyperplasia, endothelitis, fibroproliferation, collagen deposition, and luminal occlusion of the small airways, the central events seen during chronic lung allograft rejection. Briefly, monoclonal antibodies (mAbs) against strain specific MHC class I antigens were administered intrabronchially into the native lungs of 3 different strains of mice — BALB/C, C57BL/6, and HLA transgenic C57BL/6 mice on days 1, 2, 3, and 6, and then weekly thereafter. Abs of the same isotype (C1.18.4) and anti-keratin Abs were administered in control animals. By day 15, histopathological analysis of the anti-MHC class I Ab administered lung tissue revealed the presence of peribronchial and perivascular mononuclear infiltrates, epithelial hyperplasia, and fibrosis. By day 30, there was an increase in cellular infiltration around vessels and bronchioles. There was also an increase in fibrosis along with lumen occlusion of the small airways. In contrast, there was no evidence of cellular infiltration, epithelial hyperplasia, or fibrosis in the isotype or anti-keratin Ab treated animals. Immunohistochemical studies revealed the presence of CD4+ and CD11b+ cells around the bronchioles and vessels at both day 15 and day 30 in anti-MHC class I Ab administered mice.

The binding of anti-MHC class I Abs to their target induced up-regulation of inflammatory chemokines, growth factors, and cytokines which favors the recruitment of inflammatory cells into the organ. The ligation of MHC class I molecules expressed on the lung parenchyma with Abs significantly increased the expression of proinflammatory cytokines, chemokines, and their receptors along with increased bone morphogenetic protein (BMP) and fibroblast growth factor (FGF) families of growth factors.

In our murine model, IL-17 has been shown to be a potent proinflammatory cytokine that acts on epithelial cells, airway endothelial cells, and fibrocytes, leading to a proinflammatory signal which results in enhanced proinflammatory cytokine and chemokine secretion (Jovanovic et al., 1998). IL-17 has also been shown to play a crucial role in the induction of humoral autoimmune responses (Irmler et al., 2007). Our studies demonstrate that there is a significant increase in the frequency of IL-17 producing T cells against K-α1T and ColV in lung infiltrating T cells of mice administered with anti-MHC Abs. Therefore, IL-17 produced by the T cells may play an important role in the production of autoantibodies seen in the mice following administration of anti-MHC Abs (Fukami et al., 2009).

Figure 1. Proposed mechanism for chronic rejection.

Figure 1. Proposed mechanism for chronic rejection.

Towards an Unifying Model

A unifying model towards the precise understanding of the immunopathogenesis of chronic rejection is yet to be established. However, based on our finding, we propose that, following transplantation, there is an inflammatory milieu within the allograft that promotes allo-antigen presentation through both direct and indirect pathways (Figure 1). In addition, inflammation, cell death mediated by alloimmunity, and tissue remodeling following transplantation can also lead to the exposure of cryptic, but immunogenic, self-antigens or their determinants. Epitope spreading and activation of autoreactive “low-affinity” T cells that escaped the thymic deletion may play a crucial role in promoting allograft rejection. Under normal conditions, regulatory T cells (Tregs) can inhibit both autoreactive as well as alloreactive effector T cells. However, currently used immunosuppressants have effects on both effector T cells and more profoundly Tregs and therefore can facilitate loss of peripheral tolerance to self antigens. This can lead to immune responses to self antigens which either alone or in combination with alloimmune responses can lead to the pathogenesis of chronic rejection.

Conclusion

Establishment of a causal relationship between alloimmune responses and development of de novo autoimmunity to self-antigens in the post-transplant period is documented in this review. Tissue inflammation, cell death mediated by alloimmune responses, and subsequent tissue remodeling can result in exposure of self-antigens and their antigenic determinants, leading to post-transplant autoimmunity. We propose that identifying immune responses to donor mismatched HLA antigens prior to development of immune responses to self-antigens may provide new strategies to monitor and prevent the development of chronic rejection. Immunosuppressive strategies which have the potential to inhibit the Th-17 pathway and the IL-17 production may offer a future direction to improve the long-term graft survival devoid of chronic rejection.

Acknowledgment

We thank Ms. Billie Glasscock for her assistance in preparation of this manuscript.

(Corresponding author: T. Mohanakumar, Ph.D., Department of Surgery, Washington University School of Medicine, Box 8109, 3328 CSRB, 660 S. Euclid Ave., St Louis, MO 63110, USA.)

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