Identification and therapeutic management of highly sensitized patients undergoing renal transplantation.

Sensitization is generally referred to as the development of alloantibodies, specifically anti-human leukocyte antigen (HLA) immunoglobulin G (IgG) antibodies, most commonly caused by pregnancy, blood transfusion or a previous transplant. Despite being a well known phenomenon, there has not been a general consensus on its definition, monitoring or management. Today, 25% of the patients waitlisted for kidney transplant in the US have a panel reactive antibody (PRA) of >10% while, in the Eurotransplant zone, 14% have a PRA of >5%. Sensitized patients have more difficulty in finding a well HLA-matched donor, and have a higher risk of experiencing longer waiting times, more rejection episodes and eventually inferior long-term graft or patient survival. We review the currently available strategies in identifying and managing highly sensitized patients undergoing renal transplantation. We discuss the progress and limitations in laboratory techniques to elaborate on challenges in defining sensitized patients. The main management options (i.e. the Acceptable Mismatch Program, donor exchange programmes and the desensitization approach) and their mechanisms, related policies, advantages and outcomes, as well as medications and methods being investigated, are updated. In addition, particular emphasis is given to sensitization prevention, a practice that is neglected with our increasing ability to suppress the immune system (read more)

Preformed Donor HLA-DP-Specific Antibodies Mediate Acute and Chronic Antibody-Mediated Rejection Following Renal Transplantation

Donor-specific HLA alloantibodies may cause acute and chronic antibody-mediated rejection (AMR) and significantly compromise allograft survival. The clinical relevance of antibodies directed against some HLA class II antigens, particularly HLA-DP, is less clear with conflicting reports on their pathogenicity. We report two patients with high levels of pretransplant donor-specific HLA-DP antibodies who subsequently developed recurrent acute AMR and graft failure. In both cases, there were no other donor-specific HLA alloantibodies, suggesting that the HLA-DP-specific antibodies may be directly pathogenic (read more)

The humanized anti-HLA-DR moAb, IMMU-114, depletes APCs and reduces alloreactive T cells: implications for preventing GVHD

In contrast to the conventional immunosuppressive agents and nonselective T-cell-depleting antibodies, selective depletion of donor alloreactive T cells and/or host APCs, particularly DCs, represents a novel approach that can effectively control GVHD with less or no impairment of T-cell-mediated antiviral and GVL immunity. Here we report that IMMU-114, a humanized anti-human leukocyte antigen-DR (HLA-DR) moAb, efficiently depleted human PBMCs of all APCs, including B cells, monocytes, myeloid DC type-1 (mDC1), mDC2 and plasmacytoid DCs (pDCs). Early and late apoptosis of mDC1, mDC2 and pDCs, and late apoptosis of all APC subsets, were increased by IMMU-114 treatment. Although IMMU-114 had little, if any, effect on the survival and apoptosis of non-B lymphocytes (>80% of which are T cells and ~1-2% of T cells express HLA-DR), it selectively inhibited the proliferation of purified HLA-DR⁺ T cells rather than HLA-DR⁻ T cells. As a consequence, IMMU-114 treatment resulted in suppressed T-cell proliferation and reduced CD25⁺ alloreactive T cells in allogeneic MLRs. Given the critical roles of APCs and alloreactive T cells in the pathogenesis of GVHD, these results suggest that IMMU-114 may have therapeutic potential against GVHD (read more)

Patterns of De Novo Allo B Cells and Antibody Formation in Chronic Cardiac Allograft Rejection After Alemtuzumab Treatment

Even though the etiology of chronic rejection (CR) is multifactorial, donor specific antibody (DSA) is considered to have a causal effect on CR development. Currently the antibody-mediated mechanisms during CR are poorly understood due to lack of proper animal models and tools. In a clinical setting, we previously demonstrated that induction therapy by lymphocyte depletion, using alemtuzumab (anti-human CD52), is associated with an increased incidence of serum alloantibody, C4d deposition and antibody-mediated rejection in human patients. In this study, the effects of T cell depletion in the development of antibody-mediated rejection were examined using human CD52 transgenic (CD52Tg) mice treated with alemtuzumab. Fully mismatched cardiac allografts were transplanted into alemtuzumab treated CD52Tg mice and showed no acute rejection while untreated recipients acutely rejected their grafts. However, approximately half of long-term recipients showed increased degree of vasculopathy, fibrosis and perivascular C3d depositions at posttransplant day 100. The development of CR correlated with DSA and C3d deposition in the graft. Using novel tracking tools to monitor donor-specific B cells, alloreactive B cells were shown to increase in accordance with DSA detection. The current animal model could provide a means of testing strategies to understand mechanisms and developing therapeutic approaches to prevent chronic rejection (read more).

Clinical and pathological analysis of transplant glomerulopathy cases

Transplant glomerulopathy (TG) is involved in the criteria of chronic active antibody-mediated rejection (c-AMR) in Banff ‘09 classification.
Patients : TG was diagnosed in 58 renal allograft biopsy specimens (BS) from 37 renal transplant patients.
Results : Among 58 BS of TG, 27 BS were mild (cg1), 16 were moderate (cg2), and 15 were severe (cg3). Peritubular capillaritis was present in 49 (84%), transplant glomerulitis was seen in 47 BS (81%), interstitial fibrosis and tubular atrophy in 47 (81%) and the thickening of the peritubular capillary (PTC) basement membrane (PTCBM) in 44 (76%), and interstitial inflammation was present in 26 BS (45%). C4d deposition in PTC was presented in 32 BS (55%). The circulating anti-HLA alloantibody was detected in 38 times (76%), of which 27/38 (54%) were donor-specific antibodies. Deterioration of renal allografts’ function after biopsies was seen in 12 patients (32%) with six of them lost their graft.
Conclusions : We suggest that histopathological changes of TG accompanying by transplant glomerulitis, peritubular capillaritis, the thickening of the PTCBM, and circulating anti-HLA antibodies might indicate c-AMR, even if C4d deposition in PTC is negative. The prognosis of the graft exhibiting TG was relatively good under the present immunosuppression protocol in short time (read more).

Acute vascular rejection after renal transplantation and isolated v-lesion

Histopathological changes of acute vascular rejection (AVR) are characterized by intimal arteritis and transmural arteritis. According to the Banff 1997 classification, the quantitative criteria for intimal arteritis (v score) are classified: v0, v1, v2, and v3. According to Banff ‘09 classification, AVR may fall into one of four categories: acute T cell-mediated rejection (ATMR) Type IIA, ATMR Type IIB, ATMR Type III, and acute antibody-mediated rejection (AAMR) Type III.

Both cellular and humoral immunity play roles in vascular rejection, and in some cases, AVR may be provoked by anti-donor antibodies. Anti-rejection therapies were effective in most of the v1 cases but were less effective in the v2 cases and were ineffective in the v3 cases. Some reports have indicated that the prognosis of grafts exhibiting AVR is poor, but in our series, the outcome of AVR was relatively good using recent immunosuppressive protocols.

A definition for “isolated v-lesion” was originally characterized by arteritis with minimal interstitial inflammation and tubulitis. The 11th Banff conference was concluded that “isolated v1-lesions” comprised two types, T cell-mediated rejection and injury, and did not have any independent prognostic significance. However, we speculate that “isolated v-lesion” might be regarded as AAMR and ATMR (read more).

Significance of C4d deposition in antibody-mediated rejection

The C4d staining as a special tissue marker for humoral immunity has served criteria of pathological diagnosis for antibody-mediated rejection (ABMR) in Banff classification since 2003. However, the sensitivity and specificity of C4d staining have been questioned, and recently, C4d-negative ABMR has been more focused in renal allograft pathology. The aim of this study was to make certain of C4d staining for ABMR that was diagnosed by clinical and morphological findings. C4d staining was employed by immunofluorescence. This study included 14 patients with acute ABMR and 16 with chronic active ABMR. Eight of acute ABMR were ABO-blood-type-incompatible renal transplantation (ABOinRTx) pre-treated by DFPP and splenectomy or rituximub. In acute ABMR after ABOinRTx, C4d staining along peritubular capillary (PTC) was positive in five of them (62.5%). Only one graft biopsy of five acute ABMR with donor-specific antibody (DSA) showed C4d positive. We assembled 16 graft biopsies showing typical transplant glomerulopathy and thickened PTC basement membrane with peritubular capillaritis as a suspicious pathological chronic active ABMR. Four of eight DSA-positive patients were C4d negative in PTC; however, three of four DSA-positive and C4d-negative patients in PTC chronic active ABMR were C4d positive in only glomerular capillaries. C4d positivity could not come to a specific marker of ABMR diagnosing based on clinically and ordinary morphological findings (read more).