Pathology of C4d-negative antibody-mediated rejection in renal allografts.

PURPOSE OF REVIEW: To summarize current evidence supporting the existence of C4d-negative antibody-mediated rejection (AMR) in renal allografts, its potential to cause chronic graft injury, and whether histopathologic features of C4d-negative AMR differ from those of C4d-positive AMR. RECENT FINDINGS: Recently published molecular, clinicopathologic, and ultrastructural studies provide strong evidence that microvascular injury in the presence of donor-specific alloantibodies (DSA) has the potential to cause interstitial fibrosis/tubular atrophy, transplant glomerulopathy, and graft loss, whether or not peritubular capillary (PTC) C4d is present. Although C4d-positive AMR may represent a more severe form of AMR, recent studies have found that in patients with DSA, microvascular injury (glomerulitis, peritubular capillaritis) is more strongly associated with graft loss than C4d deposition. Our data suggest that C4d-positive and C4d-negative AMR show similar degrees of glomerulitis and peritubular capillaritis, similar frequencies of concurrent cell-mediated rejection, and that both may occur early or late posttransplantation. SUMMARY: In renal allografts, microvascular injury in the presence of DSA but with negative C4d staining in PTC nonetheless is indicative of humorally mediated graft injury that has the potential to cause tubular atrophy/interstitial fibrosis, transplant glomerulopathy, and graft loss. Prompt treatment for AMR may prevent or at least delay subsequent development of transplant glomerulopathy.

Reliability of whole slide images as a diagnostic modality for renal allograft biopsies.

The use of digital whole slide images (WSI) in the field of pathology has become feasible for routine diagnostic purposes and has become more prevalent in recent years. This type of technology offers many advantages but must show the same degree of diagnostic reliability as conventional glass slides. Several studies have examined this issue in various settings and indicate that WSI are a reliable method for diagnostic pathology. Since transplant pathology is a highly specialized field that requires not only accurate but rapid diagnostic evaluation of biopsy materials, this field may greatly benefit from the use of WSI. In this study, we assessed the reliability of using WSI compared to conventional glass slides in renal allograft biopsies. We examined morphologic features and diagnostic categories defined by the Banff 07 Classification of Renal Allograft Pathology as well as additional morphologic features not included in this classification scheme. We found that intraobserver scores, when comparing the use of glass slides versus WSI, showed substantial agreement for both morphologic features (κ = 0.68) and acute rejection diagnostic categories (κ = 0.74). Furthermore, interobserver reliability was comparable for morphologic features (κ = 0.44 [glass] vs 0.42 [WSI]) and acute rejection diagnostic categories (κ = 0.49 [glass] vs 0.51 [WSI]). These data indicate that WSI are as reliable as glass slides for the evaluation of renal allograft biopsies.

Tolerance to MHC class II disparate allografts through genetic modification of bone marrow.

Induction of molecular chimerism through genetic modification of bone marrow is a powerful tool for the induction of tolerance. Here, we demonstrate for the first time that expression of an allogeneic MHC class II gene in autologous bone marrow cells, resulting in a state of molecular chimerism, induces tolerance to MHC class II mismatched skin grafts, a stringent test of transplant tolerance. Reconstitution of recipients with syngeneic bone marrow transduced with retrovirus encoding H-2I-A(b) (I-A(b)) resulted the long-term expression of the retroviral gene product on the surface of MHC class II-expressing bone marrow-derived cell types. Mechanistically, tolerance was maintained by the presence of regulatory T cells, which prevented proliferation and cytokine production by alloreactive host T cells. Thus, the introduction of MHC class II genes into bone marrow-derived cells through genetic engineering results in tolerance. These results have the potential to extend the clinical applicability of molecular chimerism for tolerance induction.

Avaliação da doença vascular do enxerto no transplante cardíaco: experiência de um centro brasileiro / Assessment of cardiac allograft vasculopathy in cardiac transplantation: experience of a Brazilian center

FUNDAMENTO: O transplante cardíaco continua sendo o tratamento de escolha para a insuficiência cardíaca refratária ao tratamento otimizado. Dois métodos diagnósticos apresentam elevada sensibilidade no diagnóstico de episódios de rejeição ao enxerto e Doença Vascular do Enxerto (DVE), causas importantes de mortalidade no pós-transplante. OBJETIVO: Avaliar a relação entre os resultados do ultrassom intracoronariano (USIV) e os laudos das biópsias endomiocárdicas (BX) no seguimento de pacientes submetidos a transplante cardíaco em um serviço de referência brasileiro. MÉTODOS: Foi realizado um ensaio epidemiológico retrospectivo observacional, com pacientes submetidos a transplante cardíaco ortotópico, no período de 2000 a 2009. Foram analisados os prontuários desses pacientes e os resultados dos USIV e BX realizados rotineiramente no seguimento clínico pós-transplante e terapêutica em uso. RESULTADOS: Dos 77 pacientes analisados, 63,63% são do sexo masculino, nas faixas etárias de 22 a 69 anos. Quanto aos resultados dos USIV, 33,96% foram classificados em Stanford classe I, e 32,08%, como Stanford IV. Dos 143 laudos das biópsias, 51,08% tiveram resultado 1R, 3R em 0,69% dos laudos, e 14,48% apresentaram a descrição de efeito Quilty. Todos usaram antiproliferativos, 80,51% usaram inibidores da calcineurina e 19,48% usaram inibidores do sinal de proliferação (ISP). CONCLUSÃO: A avaliação dos pacientes pós-transplante cardíaco por meio do USIV incorpora informações detalhadas para o diagnóstico precoce e sensível da DVE, que são complementadas pelas informações histológicas fornecidas pelas BX, estabelecendo uma possível relação causal entre a DVE e os episódios de rejeição humoral.

BACKGROUND: Cardiac transplantation continues to be the treatment of choice for heart failure refractory to optimized treatment. Two methods have high sensitivity for diagnosing allograft rejection episodes and cardiac allograft vasculopathy (CAV), important causes of mortality after transplantation. OBJECTIVE: To assess the relationship between intravascular ultrasound (IVUS) results and endomyocardial biopsy (BX) reports in the follow-up of patients undergoing cardiac transplantation in a Brazilian reference service. METHODS: A retrospective epidemiological observational study was carried out with patients undergoing orthotopic cardiac transplantation from 2000 to 2009. The study assessed the medical records of those patients and the results of the IVUS and BX routinely performed in the clinical post-transplant follow-up, as well as the therapy used. RESULTS: Of the 77 patients assessed, 63.63% were males, their ages ranging from 22 to 69 years. Regarding the IVUS results, 33.96% of the patients were classified as Stanford class I, and 32.08%, as Stanford class IV. Of the 143 BX reports, 51.08% were 1R, and 0.69%, 3R. The Quilty effect was described in 14.48% of the BX reports. All patients used antiproliferative agents, 80.51% used calcineurin inhibitors, and 19.48% used proliferation signal inhibitors. CONCLUSION: The assessment of cardiac transplant patients by use of IVUS provides detailed information for the early and sensitive diagnosis of CAV, which is complemented by histological data derived from BX, establishing a possible causal relationship between CAV and humoral rejection episodes.

Análise sociodemográfica e clínica de pacientes submetidos ao transplante alogênico de células-troncos hematopoiéticas / Sociodemographic and clinical analysis of patients subjected to allogeneic hematopoietic stem cell transplantation

Objetivo: Descrever os achados clínicos e sociodemográficos dos pacientes submetidos ao transplante de células-tronco hematopoiéticas (TCTH) e encaminhados à Faculdade de Odontologia da Universidade Federal de Minas Gerais (FO-UFMG). Metodologia: Foram selecionados 39 pacientes pré-TCTH alogênico entre 2006 e 2008. Os dados sociodemográficos e clínicos foram obtidos dos prontuários médicos do dia - 7 ao dia +360 pós-TCTH. Resultados: Foi possível observar que 59% dos pacientes eram homens, 25,6% eram melanoderma e 53,8% eram solteiros. Trinta e três por cento deles possuíam o ensino fundamental, 38,5% eram católicos e 56,4% residiam em casa, sendo que (51,2%) residem em casa própria e, (61,5%) em zona urbana. O saneamento básico estava presente em 64,1%, a coleta seletiva em 69,2% e a água encanada em 64,1%. A medula óssea foi a fonte de células-tronco para o TCTH usada em 61,5% dos casos, a doença de base mais prevalente foi a leucemia (46,4%) e 41% dos pacientes foram a óbito após o TCTH. Além disso, 43,6% dos pacientes apresentaram a doença do enxerto contra o hospedeiro aguda (DECHa) e 62,5% DECHc sistêmica e 58,3% DECHc bucal. Conclusão: Assim, este estudo adiciona ao conhecimento no contexto do TCTH dados referentes ao perfil clínico e sociodemográfico dos pacientes e com isso, sugere que o êxito do transplante compreende na sinergia de todos os aspectos referentes ao transplantado.

Objective: To describe the clinical and sociodemographic findings of the patients subjected to hematopoietic stem cell transplantation (HSCT) and referred to the School of Dentistry of the Federal University of Minas Gerais (FO-UFMG). Method: Thirty-nine pre-allogeneic HSCT patients were selected between 2006 and 2008. The clinical and sociodemographic data were obtained from the medical charts from day -7 to day +360 post-HSCT. Results: It was found that 59% of the patients were male, 25.6% were Black and 53.8% were single. Thirty-three percent of them completed the elementary school, 38.5% were Catholic and 56.4% lived at home; of these, 51.2% owned their houses and 61.5% lived in the urban area. As much as 64.1%, 69.2%, 64.1% of the patients had access to basic sanitation, selective collection of residues and water supply pipelines. The bone marrow was the source of stem cells for the HSCT used in 61.5% of the cases, leukemia was the most prevalent base disease (46.4%), and 41% of the patients died after HSCT. Additionally, 43.6% of the patients presented acute graft-versus-host disease (GVHD), 62.5% presented chronic systemic GVHD, and 58.3% presented oral GVHD. Conclusion: This study adds to the knowledge of HSCT information about the clinical and sociodemographic profile of the patients, suggesting that the success of transplantation encompasses the synergy of all aspects associated with the transplant recipient.

Effects of alkaloid sinomenine on levels of IFN-γ, IL-1ß, TNF-α and IL-6 in a rat renal allograft model.

AIMS: To evaluate the immunosuppressive efficacy of alkaloid sinomenine (SIN) and the synergistic effects in combination with cyclosporin A (CsA) in acute rejection after rat renal allograft. MATERIALS & METHODS: Animals were treated with saline in group 1, SIN (30 mg/kg/d) in group 2, CsA (2.5 mg/kg/d) in group 3 and SIN (30 mg/kg/d) + CsA(2.5 mg/kg/d) in group 4. Another 12 syngeneic renal transplantation animals were treated with saline as control. Survival time is observed. The levels of serum creatinine (Scr) and blood urea nitrogen (Bun) were detected; the secretion of IFN-γ, IL-1ß, TNF-α and IL-6 were detected by ELISA. The kidneys were fixed to perform histological staining. RESULTS: The mean survival time was 8.00 ± 2.10 days in group 1, 10.67 ± 1.21 days in group 2, 11.00 ± 1.41 days in group 3 and 19.67 ± 2.80 days in group 4, while all the recipients survived more than 180 days in the control group. The 24-h urinary volume and urinary time of the other three groups were increased significantly compared with group 1. The levels of Scr and Bun, levels of IFN-γ, IL-1ß, TNF-α and IL-6 were significantly higher in group 1 than that in the other three groups; there were significant differences between group 4 and group 2 or 3. CONCLUSION: Our study showed that SIN had immunosupression effects in rat renal allograft models, it also had a synergistic effect in combination with CsA, which provided a new immunosuppressant for clinical application.

Assessment of cardiac allograft vasculopathy in cardiac transplantation: experience of a Brazilian center.

BACKGROUND: Cardiac transplantation continues to be the treatment of choice for heart failure refractory to optimized treatment. Two methods have high sensitivity for diagnosing allograft rejection episodes and cardiac allograft vasculopathy (CAV), important causes of mortality after transplantation. OBJECTIVE: To assess the relationship between intravascular ultrasound (IVUS) results and endomyocardial biopsy (BX) reports in the follow-up of patients undergoing cardiac transplantation in a Brazilian reference service. METHODS: A retrospective epidemiological observational study was carried out with patients undergoing orthotopic cardiac transplantation from 2000 to 2009. The study assessed the medical records of those patients and the results of the IVUS and BX routinely performed in the clinical post-transplant follow-up, as well as the therapy used. RESULTS: Of the 77 patients assessed, 63.63% were males, their ages ranging from 22 to 69 years. Regarding the IVUS results, 33.96% of the patients were classified as Stanford class I, and 32.08%, as Stanford class IV. Of the 143 BX reports, 51.08% were 1R, and 0.69%, 3R. The Quilty effect was described in 14.48% of the BX reports. All patients used antiproliferative agents, 80.51% used calcineurin inhibitors, and 19.48% used proliferation signal inhibitors. CONCLUSION: The assessment of cardiac transplant patients by use of IVUS provides detailed information for the early and sensitive diagnosis of CAV, which is complemented by histological data derived from BX, establishing a possible causal relationship between CAV and humoral rejection episodes.

Mineralocorticoid receptor antagonism and aldosterone synthesis inhibition do not improve glomerulosclerosis and renal interstitial fibrosis in a model of chronic kidney allograft injury.

Chronic allograft injury (CAI) is a major cause of late graft failure with a multifactorial pathogenesis; however, in different experiments an inhibition of the renin-angiotensin system by angiotensin-converting enzyme inhibitors and angiotensin II type 1 receptor blockers ameliorated the progression of chronic renal disease. Different concepts supposed that aldosterone is involved in development and/or progression of renal diseases via interaction with a non-epithelial mineralocorticoid receptor (MR), e.g. reducing neointima formation. Our examinations therefore targeted on the effects of the aldosterone synthase inhibitor fadrozole and the MR antagonist spironolactone compared to vehicle in an established rat model of CAI. In our model of CAI, neither the aldosterone biosynthesis inhibitor nor a direct MR blockade had a positive effect on renal CAI in rats. Fadrozole- and spironolactone-treated animals demonstrated a higher proteinuria value, pathologically elevated potassium values, higher tubulointerstitial damage and markedly increased heart weight/body weight as compared to vehicle. Our observations also suggest that inhibition of the MR or the biosynthesis itself had a bad influence on the amount of sclerotic glomeruli and tubulointerstitial damage. The positive effects of inhibition of aldosterone as described in cardiac models could not yet be detected in kidney recipients.

Novel histologic scoring system for long-term allograft fibrosis after liver transplantation in children.

The existing systems for scoring fibrosis were not developed to evaluate transplanted livers. Our aim was to design and validate a novel fibrosis scoring system specifically adapted to assess liver allograft fibrosis (LAF). Clinical data, histology, transient elastography (TE) and AST/platelet ratio index (APRI) were reviewed in 38 pediatric liver transplant (LT) recipients. Protocol liver biopsies performed at 6 months and 7 years post-LT were reviewed by three pathologists who assessed LAF using the METAVIR and Ishak systems. LAF was also scored separately in portal (0-3), sinusoidal (0-3) and centrolobular areas (0-3). Scoring evaluations were correlated with fibrosis quantification using morphometry, and also with TE and APRI. Statistical correlations between morphometry and METAVIR were 0.571 (p < 0.000) and 0.566 (p < 0.000) for the Ishak system. The novel score (0-9) for separate assessment of portal, sinusoidal and centrolobular fibrosis showed a better correlation with morphometry (0.731; p < 0.000) and high intra-/interobserver agreement (0.966; p < 0.000 and 0.794; p < 0.000, respectively). No correlation was found between TE or APRI and morphometry or the three histologic scores. In conclusion, this novel semiquantitative fibrosis scoring system seems to more accurately reflect LAF than the existing scoring system and may become a practical tool for staging fibrosis in LT.

Histological assessment of mechanoreceptors in Achilles allografts after anterior cruciate ligament reconstruction.

BACKGROUND: There is a lack of histological studies investigating the presence of mechanoreceptors in anterior cruciate ligament (ACL) allografts. HYPOTHESIS: Mechanoreceptors would not grow in Achilles allografts after ACL reconstruction. STUDY DESIGN: Case series study; Level of evidence, 4. METHODS: Tissue samples were obtained from 11 patients who underwent ACL reconstruction using Achilles tendon allografts. They underwent biopsies during second-look arthroscopies. The mean period from ACL reconstruction to harvesting tissue was 26.63 months (range, 12-120 months). The control group consisted of 2 normal ACLs procured from 42- and 45-year-old men who underwent amputation above the knee due to trauma. RESULTS: Ruffini corpuscles and free nerve endings were shown to be present in the specimens of the control group by processing hematoxylin-eosin stains and immunohistochemical stains with monoclonal antibodies against S-100. In the Achilles allografts, mechanoreceptors were not observed. However, fibroblasts, collagen fibers, and vessels that were not present in fresh-frozen Achilles allografts before surgery were observed. CONCLUSION: The results demonstrate that Achilles tendon allografts appeared similar to normal ligaments except for the lack of histological evidence of mechanoreceptors. In other words, there are no newly ingrown mechanoreceptors in ACL allografts.

Allograft rejection is restrained by short-lived TIM-3+PD-1+Foxp3+ Tregs.

Tregs play a pivotal role in inducing and maintaining donor-specific transplant tolerance. The T cell immunoglobulin and mucin domain-3 protein (TIM-3) is expressed on many fully activated effector T cells. Along with program death 1 (PD-1), TIM-3 is used as a marker for exhausted effector T cells, and interaction with its ligand, galectin-9, leads to selective death of TIM-3+ cells. We report herein the presence of a galectin-9-sensitive CD4+FoxP3+TIM-3+ population of T cells, which arose from CD4+FoxP3+TIM-3- proliferating T cells in vitro and in vivo and were often PD-1+. These cells became very prominent among graft-infiltrating Tregs during allograft response. The frequency and number of TIM-3+ Tregs peaked at the time of graft rejection and declined thereafter. Moreover, these cells also arise in a tolerance-promoting donor-specific transfusion model, representing a pool of proliferating, donor-specific Tregs. Compared with TIM-3- Tregs, TIM-3+ Tregs, which are often PD-1+ as well, exhibited higher in vitro effector function and more robust expression of CD25, CD39, CD73, CTLA-4, IL-10, and TGF-ß but not galectin-9. However, these TIM-3+ Tregs did not flourish when passively transferred to newly transplanted hosts. These data suggest that a heretofore unrecognized graft-infiltrating, short-lived subset of Tregs can restrain rejection.

The prevalence of immunologic injury in renal allograft recipients with de novo proteinuria.

Post-transplant proteinuria is a common complication after renal transplantation; it is associated with reduced graft and recipient survival. However, the prevalence of histological causes has been reported with considerable variation. A clinico-pathological re-evaluation of post-transplant proteinuria is necessary, especially after dismissal of the term "chronic allograft nephropathy," which had been considered to be an important cause of proteinuria. Moreover, urinary protein can promote interstitial inflammation in native kidney, whether this occurs in renal allograft remains unknown. Factors that affect the graft outcome in patients with proteinuria also remain unclear. Here we collected 98 cases of renal allograft recipients who developed proteinuria after transplant, histological features were characterized using Banff scoring system. Cox proportional hazard regression models were used for graft survival predictors. We found that transplant glomerulopathy was the leading (40.8%) cause of post-transplant proteinuria. Immunological causes, including transplant glomerulopathy, acute rejection, and chronic rejection accounted for the majority of all pathological causes of proteinuria. Nevertheless, almost all patients that developed proteinuria had immunological lesions in the graft, especially for interstitial inflammation. Intraglomerular C3 deposition was unexpectedly correlated with the severity of proteinuria. Moreover, the severity of interstitial inflammation was an independent risk factor for graft loss, while high level of hemoglobin was a protective factor for graft survival. This study revealed a predominance of immunological parameters in renal allografts with post-transplant proteinuria. These parameters not only correlate with the severity of proteinuria, but also with the outcome of the graft.

Antibody-mediated rejection in the liver allograft.

PURPOSE OF REVIEW: There is increasing evidence to suggest that antibody-mediated mechanisms play a role in the pathogenesis of liver allograft rejection. This article will review the pathology of antibody-mediated rejection (AMR) focusing on recent studies which have improved our understanding of the clinicopathological features and diagnostic approaches. RECENT FINDINGS: Recent studies have investigated the patterns of immunohistochemical staining for C4d as a tissue marker of AMR in posttransplant biopsies, and have correlated these findings with other histopathological changes and with the presence of donor-specific antibodies (DSAs). These studies have highlighted the diagnostic applications and limitations of C4d immunostaining. They have also emphasized the importance of using strict criteria for defining 'pure' AMR in the liver allograft - that is, graft dysfunction associated with compatible histological findings (typically resembling biliary obstruction), the presence of DSAs and diffusely positive staining for C4d. SUMMARY: Pure AMR is relatively uncommon in ABO-compatible grafts - it should be diagnosed on the basis of strict criteria and requires treatment with antibody-depleting immunosuppression. C4d immunostaining in isolation has limited diagnostic value. However, the presence of diffuse C4d immunostaining (involving endothelium or stroma in >50% of portal tracts or sinusoids) suggests a significant component of antibody-mediated graft damage. In a person with suggestive histological features, this finding should prompt testing for DSAs. Even in the absence of typical histological features of AMR, the combined presence of DSAs and diffuse C4d positivity is associated with more frequent or severe acute and chronic rejection, which may also warrant treatment with antibody-depleting immunosuppression.

How can pathologists help to diagnose late complications in small bowel and multivisceral transplantation?

PURPOSE OF REVIEW: Intestinal transplantation (ITx) and multivisceral transplantation (MVTx) has evolved into a viable treatment option for short bowel syndrome and intestinal failure due to a variety of factors including improved immunosuppressive regimens, superior surgical and medical management, and enhanced posttransplant monitoring. RECENT FINDINGS: The transplant pathologist is a central member of the transplant team in all phases of solid organ transplantation and as such, plays an important role in the evaluation of early and late complications after ITx and MVTx. Central among the tools for the pathologist is the mucosal biopsy, used for discerning histopathological changes in the allograft. The principal complications seen in the late posttransplant phase are acute rejection, chronic rejection, infections, and a variety of other inflammatory conditions. In order to more precisely characterize these conditions, the transplant pathologist must also be able to utilize numerous other laboratory tests and panels of molecular biomarkers that serve as ancillary information to complement the biopsy impression. SUMMARY: Using this array of tools, the transplant pathologist is now able to provide rapid and precise information regarding the gastrointestinal (GI) transplant complications, a function that allows the clinical team to appropriately and successfully intervene and that helps contribute to the observed improvement in patient and graft survival.

Lung transplantation in the fischer 344-wistar kyoto strain combination is a relevant experimental model to study the development of bronchiolitis obliterans in the rat.

Chronic allograft rejection and bronchiolitis obliterans (BO) limited successful long-term outcome after lung transplantation (LTX). Reliable animal models are needed to study the pathogenesis of BO and to develop effective therapeutic strategies. The relevance of an available experimental LTX model without immunosuppression-the Fischer (F344)-Wistar Kyoto (WKY) rat strain combination-was analyzed. The kinetics of acute and chronic rejection and respective graft histopathology were described in the F344-to-WKY rat strain combination after allogeneic LTX. A modified classification of chronic lung allograft rejection was introduced to describe obliterative changes in the airways after rat LTX. Animals from Harlan Winkelmann (HW) and Charles River (CR) were examined. Within 14 days after LTX, allografts showed moderate to severe acute vascular and bronchiolar inflammation. In contrast to rats from CR, animals from HW showed a delayed acute rejection process. Mid-term phase after LTX (days 20-40) presented a "borderline form" consisting of both acute and first signs of chronic airway rejection. On postoperative day (POD) 60, first signs of airway remodelling and distinct BO were diagnosed in 80% of animals from HW. At the same time, the allografts with BO-like lesions increased up to 100% in rats from CR. The F344-to-WKY rat LTX model allows detailed assessment of all features of acute and chronic pulmonary rejection representing a clinically relevant model. However, due to breeding differences resulting in various sublines of the same rat strain, the source and husbandary history of the animals is important for analysis of immuno-mediated processes.

Overcoming memory T-cell responses for induction of delayed tolerance in nonhuman primates.

The presence of alloreactive memory T cells is a major barrier for induction of tolerance in primates. In theory, delaying conditioning for tolerance induction until after organ transplantation could further decrease the efficacy of the regimen, since preexisting alloreactive memory T cells might be stimulated by the transplanted organ. Here, we show that such "delayed tolerance" can be induced in nonhuman primates through the mixed chimerism approach, if specific modifications to overcome/avoid donor-specific memory T-cell responses are provided. These modifications include adequate depletion of CD8+ memory T cells and timing of donor bone marrow administration to minimize levels of proinflammatory cytokines. Using this modified approach, mixed chimerism was induced successfully in 11 of 13 recipients of previously placed renal allografts and long-term survival without immunosuppression could be achieved in at least 6 of these 11 animals.

Endothelial and epithelial barriers in graft-versus-host disease.

Endothelial and epithelial cells form selectively permeable barriers that separate tissue compartments. These cells coordinate movement between the lumen and tissue via the transcellular and paracellular pathways. The primary determinant of paracellular permeability is the tight junction, which forms an apical belt-like structure around endothelial and epithelial cells. This chapter discusses endothelial and epithelial barriers in graft-versus-host disease after allogeneic bone marrow transplantation, with a focus on the tight junction and its role in regulating paracellular permeability. Recent studies suggest that in graft-versus-host disease, pathological increases in paracellular permeability, or barrier dysfunction, are initiated by pretransplant conditioning and sustained by alloreactive cells and the proinflammatory milieu. The intestinal epithelium is a significant focus, as it is a target organ of graft-versus-host disease, and the mechanisms of barrier regulation in intestinal epithelium have been well characterized. Finally, we propose a model that incorporates endothelial and epithelial barrier dysfunction in graft-versus-host disease and discuss modulating barrier properties as a therapeutic approach.

Reabilitação de maxila atrófica com tecido ósseohomógeno e prótese fixa implantossuportada / Rehabilitation of atrophic maxilla with allogeneic bone grafts followed by metal ceramic fixed prosthesis

As técnicas de reconstrução óssea para maxilasatróficas têm sido aprimoradas a fim de favorecer o aumento tecidual ósseo tanto em altura como em espessura. A técnica de enxertia realizada com o uso de osso autógeno é considerada a primeira opção de tratamento pela maioria dos implantodontistas, por demonstrar capacidade osteogênica e não promover reação antigênica. Contudo, este grupo de enxerto possuilimitações, sendo as principais: morbidade nossítios doadores e disponibilidade limitada. Nos últimos anos, alternativas têm sido pesquisadas para suprir as limitações do osso autógeno. Nesses estudos, os ossos homógenos tem se destacado dos demais grupos, principalmente por possuir disponibilidade óssea ilimitada. O presente relato de caso associado à revisão da literatura tem como objetivo discutir e mostrar a viabilidade do osso homógeno como material para reconstrução de maxila atrófica. Assim, osimplantes homógenos são uma opção para reabilitação de maxilas atróficas.

The techniques of bone reconstruction for atrophicmaxillae have been improved in order to promote bone tissue growth in both height and thickness. The grafts performed with use of autogenous bone is considered the gold standardby most researchers, for demonstrating osteogenic capacity and not to promote antigenic response. However, this type of grafting is not possible to get bone tissue in large quantity for extensive renovations. In recent years, alternatives have been researched to overcome the limitations of autogenous bone. Several alternativeshave been investigated to supply the disadvantages of autogenous bone grafts. In such studies,allogeneic bone grafts which are obtained from individuals with different genetic load, but from the same species have been extensively used. They can be indicated in cases of arthrosplasty,surgical knee reconstruction, and largebone defects as well as in oral and maxillofacial reconstruction. Besides showing great applicability and biocompatibility, this type of bone isavailable in unlimited quantities. To rehabilitate atrophic maxillae an option that has been performed with high success rate is the reconstruction with bone graft followed by osseointegrated dental implants to rehabilitate the patient aestheticsand functionally. This paper aims to show thefeasibility of allogenic bone as material for reconstruction of atrophic maxilla, and subsequent rehabilitation with metal ceramic fixed prosthesis implantand dental restoration with accompanying three years through literature review and clinical case report.