**3. Pathogenesis and mechanism**

(RR) for graft loss for patients who had an episode of AMR was around 4 times as compared with patients without AMR. Importantly, even in patients without any episode of AMR, the presence of anti-HLA-DSA on the peak serum was still associated with a significantly lower graft survival as compared with patients without anti-HLA-DSA (Amico et al., 2009; Cantar‐

The recently described entity of subclinical AMR (Gloor et al., 2006; Haas et al., 2007) in which progressive morphologic lesions are found on biopsy in the absence of overt clinical rejection may account for this different course. A recent study demonstrated that subclinical AMR is a frequent finding in patients with preformed HLA-DSA (31.1% at 3 months) and is associated with worse GFR at 1 year (Loupy et al., 2009). These progressive lesions lead to chronic humoral rejection, first described in 2001 (Regele et al., 2002) and now recognized to be a distinct cause

Antibody-mediated rejection has become clinically critical because this form of rejection is usually unresponsive to conventional anti-rejection therapy, and therefore, it has been recognized as a major cause of allograft loss. Although desensitization protocols have enabled transplantation across donor-specific antibody barriers in a growing number of cases (Haas et al., 2007; Jordan, 2006), these protocols are neither consistently efficacious nor standardized. It reflects an incomplete understanding of the pathogenesis of alloantibody-induced injury as a major cause of allograft loss. Furthermore, patients treated with these modalities persist in having a high risk of multiple AMR episodes and lower graft long term survival compared to

In 1968, when kidney transplant patients were first examined for the development of anti‐ bodies after graft failure, antibodies were detected in 11 (38%) of 29 patients who had rejected

The fact that some patients in desensitization protocols developed AMR and others with similar levels of DSA at baseline did not, has remained unexplained due to the lack of detailed studies of these patients post transplant. Burns et al. (Burns et al., 2008) aimed to define the natural history of AMR in highly sensitized patients undergoing positive cross-match kidney transplantation. They found that the serum DSA level after transplantation was the major determinant of AMR. Patients who developed high levels of DSA within the first month after transplantation almost invariably developed acute humoral rejection (AHR), whereas those who maintained low levels were rejection-free. Importantly, more than half of the patients who had high levels of DSA at baseline did not develop high levels of DSA after transplantation. Almost all patients, including those who developed AMR, had a significant decrement or even disappearance of DSA early after transplantation (Gloor et al., 2004; Zachary et al., 2005). This finding that increases in DSA levels in AMR may be transient and self-limited in many patients

presents difficulties in assessing the effectiveness of therapy aimed at treating AMR.

of late graft dysfunction and loss (Gloor et al., 2007; Regele et al., 2002).

ovich et al., 2011; Lefaucheur et al., 2010).

418 Current Issues and Future Direction in Kidney Transplantation

antibody free patients.

**2. Natural course**

their grafts (Morris et al., 1969).

The pathogenesis of late renal allograft loss is heterogeneous and difficult to diagnose.

How alloantibody and complement activation promote glomerulopathy, arteriopathy and fibrosis is incompletely clear. Only in the past 7 years, a potential role of alloantibodies for chronically deteriorating graft function has been postulated.

Alloantibodies are now appreciated as important mediators of acute and chronic rejection, differing in pathogenesis, or "nature," from T cell–mediated rejection.

Alloantibodies preferentially attack a different "location," namely the peritubular and glomerular capillaries, in contrast to T cells, which characteristically infiltrate tubules and arterial endothelium.

Antibody-mediated rejection generally has a worse prognosis and requires different ap‐ proaches to treatment and prevention than the usual T cell–mediated rejection.

MICA (MHC-class-I-polypeptide-related sequence A), one of the few potential endothelialcell surface alloantigens, has been defined at the molecular level (Kooijmans-Coutinho et al.,

Current and Future Directions in Antibody-Mediated Rejection Post Kidney Transplantation

http://dx.doi.org/10.5772/55001

421

MICA is a polymorphic non-classical MHC molecule. Antibody that is specific for MICA (MHC-class-I-polypeptide-related sequence A) can be detected in renal-allograft recipients and is associated with later rejection and graft loss (Mizutani et al., 2005; Sumitran-Holgersson et al., 2002) that was demonstrated by Zou and coworkers (Zou et al., 2007) who found that antibodies against minor histocompatibility antigens such as MICA may be associated with a

Antibodies that recognize self-proteins might also contribute to graft injury. For example, autoantibody that is specific for the angiotensin II type 1 receptor, which is expressed by vascular smooth muscle, has been associated with severe hypertension, graft dysfunction and

Several studies have shown that circulating anti-HLA class I or II antibodies, either do‐ nor reactive (Worthington et al., 2003; Hourmant et al., 2005) or de novo non–donor re‐ active (Hourmant et al., 2005; Terasaki & Ozawa, 2005), are found in a substantial fraction of renal allograft recipients, and these are associated with later graft loss. Retro‐ spective studies demonstrated that de novo appearance of DSA was associated with poor graft outcome (Colvin, 2007). One study in more than 2000 patients prospectively estab‐ lished the risk of circulating alloantibodies for graft survival after 1 and 2 years (Terasa‐

B cells are not just plasma cell precursors, but represent an important population of anti‐ gen-presenting cells particularly efficient in the situation of a sensitized recipient, be‐ cause they have specific immunoglobulin as an antigen-specific receptor on their surface, which leads to efficient uptake and presentation of donor antigens to T cells (Noorch‐ ashm et al., 2006). Indeed, an increased frequency of alloantigen-specific B cells in sensi‐ tized recipients has been reported (Zachary et al., 2007). Therefore, targeting these B cells will also interfere with activation of indirectly allo-reactive T cells, which play an impor‐

In sensitized allograft recipients with DSA, sensitization has always occurred on the level of B and T cells; because B cells need T help to produce alloantibodies of IgG isotype as measured by the Luminex technology. Therefore, a combined pathogenesis of rejection must always be

However, failure to demonstrate DSA does not rule out a contribution of antibodies to the pathologic process, because absorption of antibodies by the allograft may result in a lack of circulating DSA (Martin et al., 2005). Alternatively, DSA against non-HLA anti‐ gens or HLA-DP could explain the missing ELISA reactivity in the presence of increased cytotoxic anti-B-cell reactivity and ongoing antibody-mediated rejection (Arnold et al.,

postulated, even if not all the pathologic criteria are fulfilled (Fehr et al., 2009).

fibrinoid arterial necrosis of human renal allografts (Dragun et al., 2005).

1996).

poorer graft outcome.

ki & Ozawa, 2005).

**3.2. B- lymphocytes**

tant role in chronic allograft rejection.

2005; Opelz, 2005; Zou et al., 2007).

Antibody induces rejection acutely through the fixation of complement, resulting in tissue injury and coagulation. In addition, complement activation recruits macrophages and neutrophils, causing additional endothelial injury. Antibody and complement also induce gene expression by endothelial cells, which is thought to remodel arteries and basement membranes, leading to fixed and irreversible anatomical lesions that permanently compromise graft function.

#### **3.1. Antigenic targets**

The main antigenic targets of antibody-mediated rejection are MHC molecules (both class I and class II) (Erlich et al., 2001) and the ABO blood-group antigens (Race & Sanger, 1958). MHC class I molecules are found at the surface of all nucleated cells, including endothelial cells. By contrast, the distribution of MHC class II molecules is more limited. These molecules are constitutively expressed at the surface of B cells, dendritic cells (DCs) and microvascular endothelial cells (the last applies to humans but not mice) and are expressed by other cells depending on the stimuli that they have been exposed to and their transcriptional activation. The extreme polymorphism of MHC class I and class II polypeptides (more than 1,600 alleles in humans) aids their main function, which is antigen presentation to T cells.

Production of HLA specific alloantibodies depends on exposure to HLA molecules as a consequence of pregnancy, blood transfusion or transplantation. These antibodies are mainly of the IgG class. Blood-group antigens, most importantly the A and B antigens, are carbohy‐ drate epitopes on glycolipids and glycoproteins that are present at the surface of most tissues, including erythrocytes and endothelial cells. Antibodies that are specific for A or B antigens arise 'naturally' in normal individuals who are not of the A and/or B blood group in response to antigens from the environment, and they are usually of the IgM class (Colvin & Smith, 2005).

Antibodies to class I MHC antigens can stimulate endothelial and smooth muscle proliferation and expression of FGF receptors (Bian & Reed, 2001). Soluble terminal complement compo‐ nents (C5b-9) trigger the production of FGF and PDGF by endothelial cells (Benzaquen et al., 1994). Thus antibodies and activated complement might induce gene products that promote endothelial activation and injury with consequent basement membrane duplication and arterial smooth muscle proliferation and thickening until finally, the characteristic atheroscle‐ rosis lesion of chronic rejection results in obstruction (Jin et al., 2002; Reed, 2003).

In addition to MHC molecules and blood-group antigens, minor histocompatibility antigens might also be targets of antibody-mediated rejection. Minor histocompatibility antigens, which were originally defined in mice by their ability to cause prompt skin-graft rejection, are also thought to be relevant as targets of graft-versus-host disease and as tumor antigens (Chao, 2004). In animal studies, non-MHC-specific antibodies can cause endothelial-cell apoptosis and graft rejection (Derhaag et al., 2000; Wu et al., 2002).

However, in humans, the molecular characterization of these antigens is limited.

MICA (MHC-class-I-polypeptide-related sequence A), one of the few potential endothelialcell surface alloantigens, has been defined at the molecular level (Kooijmans-Coutinho et al., 1996).

MICA is a polymorphic non-classical MHC molecule. Antibody that is specific for MICA (MHC-class-I-polypeptide-related sequence A) can be detected in renal-allograft recipients and is associated with later rejection and graft loss (Mizutani et al., 2005; Sumitran-Holgersson et al., 2002) that was demonstrated by Zou and coworkers (Zou et al., 2007) who found that antibodies against minor histocompatibility antigens such as MICA may be associated with a poorer graft outcome.

Antibodies that recognize self-proteins might also contribute to graft injury. For example, autoantibody that is specific for the angiotensin II type 1 receptor, which is expressed by vascular smooth muscle, has been associated with severe hypertension, graft dysfunction and fibrinoid arterial necrosis of human renal allografts (Dragun et al., 2005).

Several studies have shown that circulating anti-HLA class I or II antibodies, either do‐ nor reactive (Worthington et al., 2003; Hourmant et al., 2005) or de novo non–donor re‐ active (Hourmant et al., 2005; Terasaki & Ozawa, 2005), are found in a substantial fraction of renal allograft recipients, and these are associated with later graft loss. Retro‐ spective studies demonstrated that de novo appearance of DSA was associated with poor graft outcome (Colvin, 2007). One study in more than 2000 patients prospectively estab‐ lished the risk of circulating alloantibodies for graft survival after 1 and 2 years (Terasa‐ ki & Ozawa, 2005).
