**3.2. B- lymphocytes**

Antibody-mediated rejection generally has a worse prognosis and requires different ap‐

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

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

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‐

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

rosis lesion of chronic rejection results in obstruction (Jin et al., 2002; Reed, 2003).

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

and graft rejection (Derhaag et al., 2000; Wu et al., 2002).

proaches to treatment and prevention than the usual T cell–mediated rejection.

in humans) aids their main function, which is antigen presentation to T cells.

graft function.

**3.1. Antigenic targets**

420 Current Issues and Future Direction in Kidney Transplantation

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‐ tant role in chronic allograft rejection.

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

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

The combination of alloantibody, basement membrane multilamination, C4d, and duplication of the GBM has been termed the "ABCD tetrad" by Solez and colleagues (Solez et al., 2007).

antigen expressed on graft endothelium, is well documented in ABO-incompatible kidney

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

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

423

Alexandre and colleagues (Alexandre et al., 1987) initially observed accommodation in recipients of an ABO-incompatible renal allograft. Transient depletion of the circulating antibodies that are specific for these blood-group antigens at the time of transplantation allows

A rebound of antibody concentrations (primarily IgM) within the first 10 days occurs to‐ gether with rejection in 90% of cases. However, after 21 days, for the remaining grafts, there is no correlation between the occurrence of rejection and the antibody titre (Park et al., 2003; Shishido et al., 2001). Even if the antibody titre returns to pre-transplantation levels or higher, the grafts continue to function. It has been proposed that in these cases, complement regulatory proteins and/or other control mechanisms may interrupt the com‐ plement cascade distal to the generation of C4d, so the persistence of C4d on graft endo‐ thelium represents a marker for the arrest of the complement cascade rather than

As suggested by Platt (Platt, 2002), careful histologic and immunohistologic study may help to answer this question and address any potential role of complement in the accommodation process. Accommodation in ABO-incompatible grafts is not due to a change in the nature of the antibody or loss of the target antigen in the graft, because C4d is deposited in the renal

At a cellular level, accommodation may occur via multiple mechanisms, including internali‐ zation, downregulation, inactivation, and inhibition of the target antigen (Colvin & Nickeleit,

Studies in mice show that, in the absence of T-cell help, B cells that are exposed to incompatible carbohydrate antigens on allografts differentiate into cells that can produce non-complementfixing antibody which potentially competes with complement-fixing antibody, and these B

In HLA-mismatched grafts, alloantibodies can be found in the absence of clinical graft dysfunction, thereby fitting the definition of accommodation. However, patients with cir‐ culating HLA-specific antibody have a greater likelihood of later graft loss, indicating that, if accommodation occurs, then it is either transient or insufficient to prevent CAMR. Long-term, complete accommodation has not been documented for MHC mole‐ cules, and the phenomenon might therefore be partly determined by the nature of the antigen (Colvin & Smith, 2005). Accommodation may have different degrees of effective‐ ness and stability (gradations), ranging from none (hyperacute rejection), to minimal (acute rejection), substantial (chronic rejection), or complete (stable accommodation) (Col‐ vin, 2007). The minimal features that indicate transformation from accommodation to re‐ jection have yet to be defined and drugs that promote more effective accommodation

cells gradually become tolerant after prolonged exposure (Ogawa et al., 2004).

transplants (Park et al., 2003; Platt, 2002).

microcirculation.

2006; Colvin & Smith, 2005).

would potentially be useful clinically.

immediate graft survival without hyperacute rejection.

ongoing complement-mediated graft injury (Williams et al., 2004).

#### **3.3. Plasma cells**

During AMR, it is likely that a portion of the DSA found in the serum is due to ongoing antibody production by pre-existing plasma cells. In addition, the observed increase in DSA during AMR suggests that conversion of allospecific memory B cells to plasma cells also may play a role. Unfortunately, no studies of the activity of memory B cells during AMR exist. Despite this, several groups have developed protocols to treat AMR based on their presumed impact on either B cells or plasma cells (Stegall & Gloor, 2010).

#### **3.4. Presence of antibodies with good function**

It is a common observation and "complaint" that some patients with HLA antibodies have excellent kidney graft function. The exact frequency of this occurrence has been documented to be about 20% in studies of 2658 patients with functioning grafts (Terasaki et al., 2007) Thus, at any transplant center roughly 20% of patients would likely have antibodies and good function.

According to prospective studies, when 158 patients with antibodies were followed for as long as 4 years, their graft survival was 58% as compared with 81% for 806 patients without antibodies (Terasaki et al., 2007).

Significantly, the presence of antibodies did not foretell immediate or certain graft fail‐ ure. Studies by Worthington et al. (Worthington et al., 2007) have shown that the mean time from antibody development to failure for class I antibodies was 2.7 years and 3.9 years for class II antibodies. Additionally, antibodies causing humoral rejection may not appear until as many as may reach up to 13 years (Kamimaki et al., 2007), or even after 26 years (Weinstein et al., 2005) posttransplant. The reason for this long interval between antibody appearance and graft failure is the time needed for the endothelial walls of ar‐ teries to hypertrophy and close the lumen, or for the tubules to disappear because of peritubular capillary damage produced by antibodies (Shimizu et al., 2002). In both in‐ stances, defense mechanisms could be triggered as the endothelium is damaged and re‐ pair mechanisms are triggered (Jin et al., 2005).
