Composite tissue allotransplantation (CTA) is a recently introduced option for limb replacement and reconstruction of tissue defects. As with other allografts, CTA can undergo immune‐mediated ...rejection; therefore standardized criteria are required for characterizing and reporting severity and types of rejection. This article documents the conclusions of a symposium on CTA rejection held at the Ninth Banff Conference on Allograft Pathology in La‐Coruňa, Spain, on 26 June 2007, and proposes a working classification, the Banff CTA‐07, for the categorization of CTA rejection. This classification was derived from a consensus discussion session attended by the first authors of three published classification systems, pathologists and researchers from international centers where clinical CTA has been performed. It was open to all attendees to the Banff conference. To the extent possible, the format followed the established National Institutes of Health (NIH) guidelines on Consensus Development Programs. By consensus, the defining features to diagnose acute skin rejection include inflammatory cell infiltration with involvement of epidermis and/or adnexal structures, epithelial apoptosis, dyskeratosis and necrosis. Five grades of severity of rejection are defined. This classification refines proposed schemas, represents international consensus on this topic, and establishes a working collective classification system for CTA reporting of rejection in skin‐containing CTAs.
This report documents the conclusions of an international symposium on Composite Tissue Allograft (CTA) rejection held at the Ninth Banff Conference on Allograft Pathology in La‐Coruna, Spain on June 26, 2007 and proposes a working classification, the Banff CTA‐07, for the categorization of CTA rejection.
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BFBNIB, FZAB, GEOZS, GIS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, SBMB, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
The prevalence and long‐term impact of T cell–mediated rejection (TCMR) is poorly defined in the modern era of tacrolimus/mycophenolate‐based maintenance therapy. This observational study evaluated ...775 kidney transplant recipients with serial histology and correlated TCMR events with the risk of graft loss. After a ~30% incidence of a first Banff Borderline or greater TCMR detected on for‐cause (17%) or surveillance (13%) biopsies, persistent (37.4%) or subsequent (26.3%) TCMR occurred in 64% of recipients on follow‐up biopsies. Alloimmune risk categories based on the HLA‐DR/DQ single molecule eplet molecular mismatch correlated with the number of TCMR events (p = .002) and Banff TCMR grade (p = .007). Both a first and second TCMR event correlated with death‐censored and all‐cause graft loss when adjusted for baseline covariates and other significant time‐dependent covariates such as DGF and ABMR. Therefore, a substantial portion of kidney transplant recipients, especially those with intermediate and high HLA‐DR/DQ molecular mismatch scores, remain under‐immunosuppressed, which in turn identifies the need for novel agents that can more effectively prevent or treat TCMR.
Histologic follow‐up after T cell‐mediated rejection demonstrates that persistent and subsequent events are common and associate with death‐censored and all‐cause graft loss after adjusting for other time‐dependent covariates. Helanterä comments on page 681.
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BFBNIB, FZAB, GEOZS, GIS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, SBMB, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
Summary
The advent of more potent immunosuppressants led to the first successful human upper extremity transplantation in 1998. At this time, >100 upper extremity transplants, 30 face transplants, ...and a variety of other vascularized composite allotransplantation (VCA) procedures have been performed around the world. VCA recipients present unique challenges for transplantation. The incidence of acute rejection exceeds 80% in hand and face transplantation and is well documented, whereas reports about antibody‐mediated rejection and chronic rejection remain scarce. Immunosuppression protocols commonly used at US centers are derived from solid organ transplantation protocols. Novel approaches to minimize rejections in VCA may include improved HLA matching and considerations toward cytomegalovirus infection status. New graft preservation techniques may decrease immunogenicity prior to transplant. Novel monitoring methods such as valid biomarkers, ultrasound biomicroscopy, and sentinel flaps may enable earlier diagnosis of rejection. Cell‐based therapies are being explored to achieve immunosuppressive regimen minimization or even tolerance induction. The efficacy of local immunosuppression in clinical VCA remains controversial. In conclusion, although immunosuppressive strategies adapted from SOT have demonstrated good midterm results, focusing on the unique features of VCA grafts may enable additional, more specific treatment strategies in the future and improved long‐term graft outcomes.
This review focuses on current standards for management of antibody-mediated rejection in solid-organ transplant recipients and emphasizes advances that may ultimately lead to the development of ...precise, pathogenesis-based therapeutic approaches.
Antibody-mediated rejection (ABMR) of renal allografts occurs in two forms. Type 1 ABMR results from persistence and/or a rebound of preexisting donor-specific antibodies in sensitized patients and ...usually occurs early post-transplantation. Type 2 ABMR is associated with de novo donor-specific antibodies and usually occurs over one year post-transplantation. It is generally accepted that types 1 and 2 also differ with regard to certain pathologic features including the frequencies of C4d positivity and concurrent cell-mediated rejection. However, direct comparison of pathologic, serologic, and clinical features of types 1 and 2 ABMR is lacking. Here we compared these features in 80 cases of ABMR (37 type 1, 43 type 2) diagnosed at our center. Compared with type 1, type 2 ABMR occurred later post-transplantation, was more often associated with donor-specific antibodies against Class II HLA, and was associated with more interstitial fibrosis/tubular atrophy and more frequent cell-mediated rejection, although these did not differ with respect to C4d positivity. By univariate analysis, graft survival was lower with type 2 than type 1 ABMR with borderline significance. Still, among these 80 patients, all but one treated for ABMR following diagnosis, the only two independent predictors of graft failure were at least moderate interstitial fibrosis/tubular atrophy and failure of the donor-specific antibody relative intensity scale score, a measure of the combined strength of all donor-specific antibodies present, to decrease in response to therapy.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
Autologous induced pluripotent stem cells (iPSCs) constitute an unlimited cell source for patient-specific cell-based organ repair strategies. However, their generation and subsequent differentiation ...into specific cells or tissues entail cell line-specific manufacturing challenges and form a lengthy process that precludes acute treatment modalities. These shortcomings could be overcome by using prefabricated allogeneic cell or tissue products, but the vigorous immune response against histo-incompatible cells has prevented the successful implementation of this approach. Here we show that both mouse and human iPSCs lose their immunogenicity when major histocompatibility complex (MHC) class I and II genes are inactivated and CD47 is over-expressed. These hypoimmunogenic iPSCs retain their pluripotent stem cell potential and differentiation capacity. Endothelial cells, smooth muscle cells, and cardiomyocytes derived from hypoimmunogenic mouse or human iPSCs reliably evade immune rejection in fully MHC-mismatched allogeneic recipients and survive long-term without the use of immunosuppression. These findings suggest that hypoimmunogenic cell grafts can be engineered for universal transplantation.
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EMUNI, FIS, FZAB, GEOZS, GIS, IJS, IMTLJ, KILJ, KISLJ, MFDPS, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, SBMB, SBNM, UKNU, UL, UM, UPUK, VKSCE, ZAGLJ
We studied the clinical, histologic, and molecular features distinguishing DSA‐negative from DSA‐positive molecularly defined antibody‐mediated rejection (mABMR). We analyzed mABMR biopsies with ...available DSA assessments from the INTERCOMEX study: 148 DSA‐negative versus 248 DSA‐positive, compared with 864 no rejection (excluding TCMR and Mixed). DSA‐positivity varied with mABMR stage: early‐stage (EABMR) 56%; fully developed (FABMR) 70%; and late‐stage (LABMR) 58%. DSA‐negative patients with mABMR were usually sensitized, 60% being HLA antibody‐positive. Compared with DSA‐positive mABMR, DSA‐negative mABMR was more often C4d‐negative; earlier by 1.5 years (average 2.4 vs. 3.9 years); and had lower ABMR activity and earlier stage in molecular and histology features. However, the top ABMR‐associated transcripts were identical in DSA‐negative versus DSA‐positive mABMR, for example, NK‐associated (e.g., KLRD1 and GZMB) and IFNG‐inducible (e.g., PLA1A). Genome‐wide class comparison between DSA‐negative and DSA‐positive mABMR showed no significant differences in transcript expression except those related to lower intensity and earlier time of DSA‐negative ABMR. Three‐year graft loss in DSA‐negative mABMR was the same as DSA‐positive mABMR, even after adjusting for ABMR stage. Thus, compared with DSA‐positive mABMR, DSA‐negative mABMR is on average earlier, less active, and more often C4d‐negative but has similar graft loss, and genome‐wide analysis suggests that it involves the same mechanisms.
Summary Sentence
In 398 kidney transplant biopsies with molecular antibody‐mediated rejection, the 150 DSA‐negative cases are earlier, less intense, and mostly C4d‐negative, but use identical molecular mechanisms and have the same risk of graft loss as the 248 DSA‐positive cases.
In a population of kidney transplant indication biopsies with a molecular diagnosis of antibody‐mediated rejection, those without compared to those with donor‐specific antibody typically occur earlier, are less active, and are more often C4d‐negative but have similar graft loss risk and, according to genome‐wide analyses, involve the same mechanisms.
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BFBNIB, FZAB, GEOZS, GIS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, SBMB, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
Late acute rejection (LAR) after liver transplantation is often associated with poor clinical outcomes. We reviewed our experience of managing LAR in the current era to determine its natural history.
...A database of 970 consecutive adult liver transplants was reviewed retrospectively. LAR was defined as histologically proven acute cellular rejection occurring more than 90 days after transplantation.
The incidence of LAR was 11%, with a mean time of 565 days (median, 311 days; range, 90-2922 days) after transplantation. The highest rates for LAR were in seronegative hepatitis (17%), primary biliary cirrhosis (16%), and primary sclerosing cholangitis (13%) with an odds ratio of 2.3, 2.1, and 1.8, respectively. Logistic regression showed that younger recipients, primary biliary cirrhosis, and previous graft loss were independent predictors of LAR (P<0.001). Mean trough whole blood tacrolimus levels were at their lowest levels 1 week before the diagnosis of rejection (5.5 ng/mL; SD, 2.6) compared with levels of 7.7 ng/mL 4 weeks before rejection, showing a clear temporal relation. Graft survival was worse in those with LAR (P<0.01), whereas the best graft survival was among early acute rejection cases (85% 10-year survival; P<0.01). Poor response to treatment correlated with the development of ductopenic rejection (r=0.3; P<0.01). Approximately half with early ductopenic rejection eventually died (n=15).
LAR continues to provide a risk to patient and graft survival: understanding risk factors may allow an improvement in monitoring and early intervention and so prevent early graft loss.
Genetically modified pig kidney xenografts were transplanted into two brain-dead human recipients. The xenografts functioned immediately and showed no evidence of acute rejection on serial biopsy ...over a period of 54 hours. The serum creatinine level decreased in both recipients.
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