**4. Accommodation**

Transplantation across an ABO barrier, which normally precipitates hyperacute rejection, has been done successfully in many centers, using special protocols to deplete naturally occurring anti–blood group antibodies.

The phenomenon of accommodation, in which the graft acquires resistance to humoral injury and continues to function well despite the continued presence of antibody against a target antigen expressed on graft endothelium, is well documented in ABO-incompatible kidney transplants (Park et al., 2003; Platt, 2002).

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).

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

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

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

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‐

Transplantation across an ABO barrier, which normally precipitates hyperacute rejection, has been done successfully in many centers, using special protocols to deplete naturally occurring

The phenomenon of accommodation, in which the graft acquires resistance to humoral injury and continues to function well despite the continued presence of antibody against a target

impact on either B cells or plasma cells (Stegall & Gloor, 2010).

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

422 Current Issues and Future Direction in Kidney Transplantation

pair mechanisms are triggered (Jin et al., 2005).

antibodies (Terasaki et al., 2007).

**4. Accommodation**

anti–blood group antibodies.

**3.3. Plasma cells**

function.

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 immediate graft survival without hyperacute rejection.

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

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 microcirculation.

At a cellular level, accommodation may occur via multiple mechanisms, including internali‐ zation, downregulation, inactivation, and inhibition of the target antigen (Colvin & Nickeleit, 2006; Colvin & Smith, 2005).

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

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 would potentially be useful clinically.
