Academic literature on the topic 'Chronic vascular rejection'

The most significant pathologic finding in chronically rejected organ grafts is diffuse concentric intimal proliferation in the arterial system. To develop a reproducible model of chronic vascular rejection in cardiac grafts which we could then use to study the pathogenesis and therapy of this disease process, we exchanged heterotopic cardiac allografts across minor histocompatibility barriers using commercially available Lewis rats as donors and F‐344 rats as recipients. We found that all long‐term surviving allografts developed diffuse graft arteriosclerotic lesions which were virtually identical in appearance to those seen in chronically rejected human cardiac grafts. Immunohistochemical studies confirm that end‐stage lesions arc similar in composition to human lesions and are made up predominantly of vascular smooth muscle cells with occasional monocytes and T cells. Analysis of continuous series of rejecting allografts demonstrates that a distinct inflammatory stage precedes smooth muscle cell accumulation in areas of intimal thickening, suggesting that mononuclear cells play a role in the developing lesion. Endothelial expression of class II and ICAM‐1 probably underlies early mononuclear cell adherence to the endothelium. Analysis using quantitative RT‐PCR and immunocytochemistry confirms MCP‐I is expressed by ED I‐positive monocyte/macrophages in rejecting cardiac grafts, suggesting this chemoattractant may help drive mononuclear cell accumulation in the expanding intima. Immunohistochemical labelling of PDGF, TNF and IL‐1β in vascular lesions suggests these factors may trigger intimal vascular smooth muscle cell proliferation in chronically rejecting allografts, as they, along with protein S, were closely associated with sites of intimal hyperplasia and smooth muscle cell proliferation. Hypercholesterolemia did not enhance the severity of lesion development in long‐term surviving allografts, suggesting that lipid levels are not a major etiologic factor in graft arteriosclerotic lesion formation in the Lewis‐F‐344 model. Placing the recipients on a diet deficient in essential fatty acids (which modulates leukocyte functions and infiltration) reduced graft infiltration by mononuclear cells and markedly diminished arterial lesion development in chronically rejecting grafts. A key role for CD4 and mononuclear cells (T cells and/or macrophages) in the initiation and amplification of the vascular response is suggested because a short course of CD4 mAb‐ targeted therapy attenuated many of the vascular sequelae of chronic allograft rejection; there was an absence of myocardial necrosis, a lack of upregulation of ICAM and class II MHC antigens, and decreased expression of TNF, IL‐Iβ, TGF‐β, PDGF and protein S expression. Our data suggest that the activated macrophage is a major force in driving the system toward accelerated atherosclerosis, and that this model should prove useful in analyzing the pathogenesis and drug therapy of chronic rejection.

Chronic rejection is characterized by morphological evidence of destruction of the transplanted organ. The injury to the organ is associated with collagenization of variable degree. The destruction and fibrosis of the organ is probably the result of 1) direct alloimmune cytotoxic injury (i.e., acute and/or ongoing rejection) of the organ tissue, and 2) end‐organ ischemic injury secondary to fibroproliferative endarteritis (i.e.. chronic vascular rejection). The cardinal morphological feature of chronic rejection in all allografts is fibroproliferative endarteritis, which is characterized by widening of the subendothelial space due to a cellular fibrosis which may have an onion‐skin appearance with a PAS or silver stain. Macrophages with foamy cytoplasm and lymphocytes may be present in this fibrotic tissue. The smooth muscle wall may show foci of fibrosis as well, if involved by previous necrotizing rejection. These features are commonly found in needle core biopsies of kidney allografts and may involve the interlobular, arcuate, and interlobar arteries. They are less commonly found in pancreatic needle biopsies, and only rarely in hepatic and pulmonary allograft biopsies, rendering the diagnosis of chronic rejection often difficult to establish. Though the vascular lesions may not be apparent in biopsies, they are typically found in explained organs where larger vessels can be examined. Thus, the diagnosis of chronic rejection may rest upon other and in some instances less specific abnormalities, usually ischemic in origin due to vascular lesions and consequent decreased perfusion of the graft. In the kidney these changes are characterized by strips of cortical atrophy (tubular atrophy, interstitial fibrosis and collapsed glomerular tufts) and infarcts, in the liver by centrolobular ballooning degeneration and canalicular cholestasis, and in the pancreas by chronic pancreatitis and infarcts. In lung allografts, the major and only reliable morphological feature of chronic rejection is bronchiolitis obliterans. Additional features of chronic rejection include onion‐skinning of glomerular capillary walls (chronic transplant glomerulopathy) in the kidney, chronic active hepatitis and paucity of bile ducts in the liver, and destruction of the islets in pancreas allografts.

As there are other lesions in the cardiac allografts of long‐term survivors, it is best to refer to the vascular lesion as “graft vascular disease”. Graft vascular disease may be evident as early as 3 months after cardiac transplantation and may cause death in the recipient as late as 22 years post‐transplant. The disease affects infants, children, and adults as well as the recipients of combined heart‐lung transplants. It is one of the most discouraging aspects of long‐term survival in combined heart‐lung and heart transplantation, accounting for 18% of the deaths among the 201 cardiac transplants performed at Stanford during the cyclosporine era. The pathology of graft vascular disease is that of a concentric intimai proliferation with minimal damage to the elastic lamina and minimal or no change in the media of the coronary vessel wall. The lesion may affect the entire length of the vessel wall as well as the branches and small branches that penetrate into the myocardium of the coronary system. These changes differ from that of naturally occurring atherosclerosis in that, instead of focal lesions developing, the whole length of the vessel is affected, including the small branches. This precludes optimal treatment with angioplasty and other therapies. Because small vessels are involved, the resulting myocardial infarcts may be patchy and small. Presently, no strong correlation has been made with usual risk factors or transplantation for end‐stage coronary atherosclerosis, cardiomyopathy or congenital heart disease. The etiology of graft coronary disease remains unclear. Studies have suggested vascular cell activation of various kinds, including cytokines. Some of these processes, however, have been found in nontransplant coronary disease as well. A correlation with acute rejection, although suspected, has not been definitively proved; in combined heart‐ lung transplantation, the cardiac graft rarely rejects and yet graft vascular disease develops. The only correlation thus far has been with cytomegalovirus (CVM) infection, in which death from graft vascular disease is higher in infected recipients. More recently, a correlation has been made with the so‐called “Quilty lesion”. Early animal studies with in vivo blockade of tumor necrosis factor (TNF) indicated that it inhibits the development of graft arteriopathy. Such studies are being conducted extensively in America and elsewhere.

The lipoprotein pattern was investigated in 46 renal transplant recipients with histologically confirmed chronic vascular rejection (CVR) as an approach to studying its role for development and progression of CVR or transplant atherosclerosis. Renal transplant patients without evidence of chronic rejection and other renal patients with varying degrees of renal function impairment and/or proteinuria served as controls. Patients with CVR had more advanced lipoprotein disturbances as compared to patients with stable graft function. CVR patients had higher VLDL, LDL and total cholesterol and triglyceride levels, a more triglyceride‐rich VLDL and LDL fraction and a more atherogenic distribution of the lipoproteins as compared to control renal transplant patients. Impaired renal function and proteinuria, which are common in CVR, explain these lipid abnormalities only in part, since patients with CVR constitute a different cluster in this respect when compared with other patients with renal dysfunction. It is concluded that lipoprotein abnormalities and oxidative modification may play a crucial role for a growth factor‐driven progression of CVR.

Notre équipe a récemment démontré que l'incapacité des cellules endothéliales du greffon à transmettre des signaux inhibiteurs dépendant des molécules HLA-I pouvait induire une activation des cellules NK circulantes du receveur par un phénomène appelé « missing self ». Cette activation, indépendante de la présence d’anticorps spécifique du donneur (ou DSA pour donor specific antibody), contribue néanmoins à la génération de lésions d’inflammation microvasculaire (MVI pour microvascular inflammation), puis de façon chronique à la destruction du greffon.Cette étude visait à décortiquer les voies de signalisation responsables de l'activation des cellules NK par missing self et à explorer le potentiel thérapeutique d'un blocage pharmacologique de ces voies.Nous avons dans un premier temps pu valider l’impact de ce nouveau rejet dans une cohorte indépendante en montrant une réduction significative de la survie des greffons, comparable à celles des patients atteints de rejet médié par les anticorps. L'analyse transcriptomique des biopsies de ces patients a révélé une surexpression cohérente des voies liées à l'inflammation, au rejet d'allogreffe, à la réponse à l'interféron gamma et à l'activité cytotoxique des cellules NK. En utilisant un modèle murin de transplantation cardiaque hétérotopique, nous avons identifié la voie mTOR comme critique pour l'activation des cellules NK induite par missing self. Cette découverte a été validée in vitro à l'aide d'un modèle dans lequel des cellules NK humaines purifiées ont été mises en coculture avec des cellules endothéliales microvasculaires glomérulaires humaines en situation de missing self. Conformément à ces résultats, l'introduction d'un inhibiteur de mTOR a permis la réduction de l'activation des cellules NK et les lésions endothéliales in vitro, ainsi qu’une diminution substantielle de l'inflammation microvasculaire in vivo.Sur la base de ces résultats expérimentaux, une étude clinique pilote a été menée auprès de 50 transplantés rénaux chez qui l'on avait diagnostiqué un rejet médié par les cellules NK induit par missing self. Nos résultats préliminaires ont confirmé l'activation de la voie mTOR dans les cellules NK infiltrant la microcirculation du greffon. En outre, l'administration d’un inhibiteur de mTOR chez 16 de ces patients s’accompagnait d’une réduction des lésions d’inflammation microvasculaire, et d’une amélioration de la survie du greffon comparé aux 34 autres patients ayant conservé le même traitement immunosuppresseur d’entretien.Cette étude translationnelle innovante suggère que l’inhibition thérapeutique de la voie mTOR est une approche prometteuse pour atténuer les lésions histologiques du rejet induit par les cellules NK activées par missing self. Ce traitement pourrait permettre de prolonger la survie des greffons, un enjeu capital face à la pénurie actuelle d’organes disponibles pour les patients en attente de transplantation
Our team recently demonstrated that the inability of graft endothelial cells to transmit HLA-I-dependent inhibitory signals could induce activation of the recipient's circulating NK cells through a phenomenon known as “missing self”. This activation, independent of the presence of donor-specific antibody (DSA), nonetheless contributes to the generation of microvascular inflammation (MVI) lesions, and then to graft chronic destruction. The aim of this study was to unravel the signaling pathways responsible for missing self-mediated NK cell activation, and to explore the therapeutic potential of the pharmacological blockade of these pathways. We were first able to validate the impact of this new rejection in an independent cohort, showing a significant reduction in graft survival comparable to those of patients with antibody-mediated rejection. Transcriptomic analysis of these patients’ biopsies revealed consistent overexpression of pathways related to inflammation, allograft rejection, interferon-gamma response and NK cell cytotoxic activity. Using a mouse model of heterotopic heart transplantation, we identified the mTOR pathway as critical for missing self-induced NK cell activation. This finding was validated in vitro using a model in which purified human NK cells were cocultured with human glomerular microvascular endothelial cells in missing-self situation. Consistent with these results, the introduction of an mTOR inhibitor led to a reduction in NK cell activation and missing self-induced endothelial cells damage in vitro, as well as a substantial reduction in microvascular inflammation in vivo. Based on these experimental results, a pilot clinical study was carried out in 50 kidney transplanted patients diagnosed with missing self-induced NK cell-mediated rejection. Our preliminary results confirmed the activation of the mTOR pathway in NK cells infiltrating the graft microcirculation. Moreover, the administration of an mTOR inhibitor in 16 of these patients was associated with a reduction in microvascular inflammatory lesions, and an improvement in graft survival compared to the 34 other patients remained under the same immunosuppressive treatment. This innovative translational study suggests that therapeutic inhibition of the mTOR pathway is a promising approach for attenuating the histological lesions of rejection induced by missing self-mediated NK cells activation. This treatment could make it possible to prolong graft survival, a crucial issue given the current shortage of organs available to patients awaiting transplantation

La transplantation d'organe est le meilleur traitement en cas de défaillance terminale d'un organe vital. Cependant, la survie sur le long terme est limitée par la perte inexorable de la fonction des greffons. Cette dernière est attribuée à l'inflammation microvasculaire (1MV) causée par la réponse anticorps contre les alloantigènes (rejet humoral chronique (RHC)). En analysant une cohorte de 129 transplantés rénaux présentant de l'1MV sur une biopsie de greffon, nous avons trouvé que, dans la moitié des cas, les lésions n'étaient pas médiées par les anticorps. Chez ces patients, des études génétiques ont révélé une prévalence plus élevée de « mismatches » entre les molécules HLA de classe 1 (HLA-1) du donneur et les « Killer-cell immunoglobulin-receptors » (K1R) inhibiteurs des NK du receveur. Nous avons émis l'hypothèse que la nature allogénique de l'endothélium du greffon pouvait créer un « pseudo-missing-self ». De ce fait, les NK du receveur, exposés à des stimuli inflammatoires, ne reçoivent plus les signaux inhibiteurs transmis par le HLA-1 de la part des cellules endothéliales du donneur. Dans un modèle de co-culture de cellules endothéliales et de NK humains, nous avons démontré que l'absence d'un ligand HLA-1 du soi sur la cellule endothéliale peut activer les NK. Cette activation dépend de la voie mTOR dans les NK, qui peut être bloquée par la rapamycine, un inhibiteur de mTORC1 disponible en clinique. Enfin, nous avons confirmé l'existence de rejets NK induit par le « missing-self » et leur sensibilité à la rapamycine dans un modèle murin de transplantation cardiaque. Notre travail identifie un nouveau type de rejet chronique, exclusivement médié par l'immunité innée, les NK, ayant le même impact délétère sur la survie des greffons que le RHC. Cependant, alors qu'il n'y a pas de traitement disponible pour le RHC, les inhibiteurs de mTOR préviennent efficacement le développement de lésions dans un modèle murin de rejet vasculaire chronique induit par le « missing self »
Organ transplantation is the best treatment for terminal organ failure. However, long-term outcome of organ transplantation remains limited by inexorable loss of graft function, which the prevalent dogma links to the microvascular inflammation (MVI) triggered by the recipient's antibody response against alloantigens (antibody-mediated chronic rejection, AMR). Analysing a cohort of 129 renal transplant patients with MVI on graft biopsy, we found that, in half of the cases, histological lesions were not mediated by antibodies. In these patients, genetic studies revealed a higher prevalence of mismatches between donor HLA-I and inhibitory Killer-cell immunoglobulin-receptors (KIR) of recipient's NK cells. We hypothesized that the allogeneic nature of graft endothelium could create a "pseudo-missing self" situation, thereby the recipient's NK cells exposed to inflammatory stimuli would not receive HLA I-mediated inhibitory signals from donor endothelial cells. In co-culture experiments with human NK cells and endothelial cells, we demonstrated that the lack of self HLA-I on endothelial cells can activate NK. This activation triggers mTOR pathway in NK, which can be blocked by rapamycin, a commercially available inhibitor of mTORC1. Finally, we confirmed the existence of missing self-induced rejection and its sensitivity to mTOR inhibition in a murine heart transplantation model. Our work identifies a new type of chronic rejection, exclusively mediated by innate NK cells, with the same detrimental impact on graft survival as AMR. However, while no therapy is available for AMR, mTOR inhibitors efficiently prevent the development of lesions in murine models of NK cell-mediated chronic vascular rejection

The purpose of imaging of the transplant kidney is to assess integrity, anatomy, and function. Relatively or actually non-invasive technologies can be used to monitor for potential early post-transplant complications such as acute tubular necrosis, acute rejection, haematoma, pyelonephritis, abscess, urinoma, ureteral obstruction, vascular complications, and rarely graft torsion. The technologies also assist in the diagnosis and management of late complications such as those arising from immunosuppression, chronic rejection, lymphocoele, cyst, renal artery stenosis, urinary obstruction, and tumours. This chapter demonstrates the capacity of the various imaging modalities such as ultrasound, computed tomography, and magnetic resonance imaging, to assist in the clinical management of the renal transplant recipient.

Adipose tissue mesenchymal stem cells (AD-MSC or ADSC) are multipotent cells that do not show immune rejection. In this work, we analyze the route of administration and its possible differentiation into specific lineages of adipogenic, chondrogenic, osteogenic, myogenic, or neurogenic phenotypes. Transplanted cells induced tissue repair by inducing angiogenic, anti-inflammatory, and immunomodulatory effects (IDO, PG-2, nitric oxide, and some cytokine signaling). The ADSC exert these tissue repair processes through the release of chemokines and growth factors in a paracrine manner. Other fat-derived stem cells such as perivascular adipose tissue cells (PVAT) and muse cells induced reparative effects. Cell-free therapy using stromal vascular fraction (SVF) or the use of exosomes releasing miRNAs and cytokines also confirmed their safety and efficacy in vitro. Several published preclinical and clinical trials with AD-MSC confirmed their beneficial effects to repair and prevent chronic-degenerative pathologies. In this chapter, we review AD-MSC-based therapies that have used preclinical rodent models of disease for cartilage repair, regeneration of the peripheral and central nervous system, dental bone, myocardium, and liver, and in the treatment of perianal fistula in Chron’s disease, and in wound and skin fibrosis repair. In addition, this work also includes clinical studies with AD-MSC or other fat-derived stem cells in patients with various pathologies.

In 17 consecutive cadaveric kidney transplant recipients F VIII:C and vWFag were repeatedly determined before transplantation and during 4 months thereafter. Graft biopsy was performed in 12 patients for deterioration of renal function. F VIII:C was determined by a one stage clotting assay using F VIII:C deficient substrate plasma. vWFag was assayed by electroimmunoassay using specific rabbit anti-human vWFag antibodies. Results of F VIII:C and vWFag are expressed referring to NHP as 100%.Results: 2/17 patients lost their graft due to irreversible vascular rejection, 2/17 patients had reversible vascular rejection, 2/17 patients developped glomerulonephritis, 6/17 patients showed acute or chronic CyA nephrotoxicity. In 5/17 patients graft biopsy was not necessary. Despite normalisation of renal function (serum creatinine levels<150umol/L) in 9 out of 17 patients F VIII:C (239 ± 66% to 408 ± 74%, mean ± SD) remained elevated in all 17 patients. vWFag (181 ± 29% to 454 ± 84%) was normalised in only 2 out of 17 patients. CyA dosis and CyA blood levels were not correlated with F VIII:C and vWFag. All 4 patients with histological vascular rejection, both patients with later developping glomerulonephritis and 3 out of 6 patients with later developping CyA nephrotoxicity showed F VIII:C/vWFag quotients > 1 (1,1 to 1,3) Four out of 5 patients with well functioning graft had F VIII:C/ vWFag quotients consistently <1 (0,68 to 0,92).Conclusion: 1. The elevated F VIII:C and vWFag levels in chronic renal failure are not normalised during 4 months of observation despite normalisation of renal function by transplantation and immunosuppression with CyA.2. A quotient F VIII :C/vWFag < 1 may indicate a good prognosis for kidney allograft function in the absence of CyA nephrotoxicity whereas later developping graft rejection or glomerulonephritis were associated with F VIII:C/vWFag>1.

The chronic administration of CyA to animals and humans to prevent graft rejection may induce renal arteriolar damage resembling hemolytic uremic syndrome (HUS). This is a syndrome of vascular damage with thrombotic occlusions of the microcirculation. Endothelial damage is considered the first event in the pathogenetic cascade leading to HUS. We have used bovine aortic endothelial cells in culture to address the issue of CyA-induced arteriolar damage. CyA-induced a time (1-24 hours) and dose (1-50 μM) dependent cell damage. CyA-induced injury was characterized by an early cell detachment followed by lysis as documented by the increase in LDH and Cr release. 1 μM CyA did not induce cell detachment and lysis was evident only after prolonged incubations. 10 and 50 μM CyA both induced marked cell detachment and lysis: lysis started 3 hours after incubation of endothelial cells with CyA and was maximal at the end of 24 hour incubation (LDH release, percent specific increase over control values: 10 μM CyA, 47%; 50 μM CyA, 70%; 51 Cr release, percent specific increase over control values: 10 μM CyA, 28%; 50 μM CyA, 34%). CyA-induced injury was associated with dose- and time-depedent increase in prostacyclin (PGI2) and thromboxane A2 (TxA2) release by endothelial cells exposed to 10 and 50 μM CyA. CyA-induced generation of PGI2 and TxA2 was inhibited when the incubations were carried-on in the presence of acetyl salicilic acid (500 μM). These studies indicate that CyA exerts a direct toxic effect on endothelial cells and might help to understand the pathogenesis of CyA-induced vascular damage.

Male breast cancer (MBC) is an uncommon disease representing only 1% of the total cases. This low incident rate could be due to the low amount of breast tissue and the hormonal differences between men and women. The Surveillance, Epidemiology and End Result (SEER) program reported that the incidence rate of breast cancer was 1.1 per 100,000 men in the mid-1970s and raised to 1.44 per 100,000 men by 2010. There are a lot of characteristics that are common to male and female breast carcinomas, especially given the fact that a lot of the factors that influence malignant changes are similar, but there are also some singularities. In this matter, it is important to understand the existence of risk factors for MBC, particularly the genetic abnormalities, such as BRCA-1 and BRCA-2 mutations. Therefore, a man with this type of predisposition is more likely to develop breast cancer, especially if submitted to an immunosuppressive therapy, normally used to prevent the rejection of transplanted organs. This study aimed to report a case of a patient with chronic alcoholism history, who later developed a liver tumor and breast cancer. This patient reported gynecomastia, which could be related to his health condition, given the fact that liver failure and cirrhosis probably started preventing the inactivation of the estrogens by the liver, causing and stimulating proliferation of the mammary tissue, and increasing the chance of gene mutations. We report a 56-year-old man with a history of smoking, chronic alcoholism, and gynecomastia with 10 years of evolution who was diagnosed with cirrhosis and liver tumor in 2014. He underwent two sessions of a chemoradiotherapy treatment, resulting in reduction of the tumor size as a result. In 2015, the patient had a liver transplant. To prevent organ rejection, it was established an immunosuppressive therapy with tacrolimus 10 mg/day and myfortic 720 mg/day. In 2016, the patient noticed a breast lump and searched for medical assistance. At the appointment, after physical examination, the presence of a 2-×2-cm lump in the right breast was confirmed. A few examinations were requested, such as ultrasonography, which showed a BIRADS4 as a result, chest tomography, and abdominal tomography. The examinations concluded that the lump had a high probability of malignancy. Then, to confirm the suspicion, it was proposed the performance of a fine-needle aspiration of the lump was followed by a core biopsy. The results showed an invasive breast carcinoma positive for estrogen receptors, negative for progesterone receptors, negative for HER-2 oncoprotein, and KI67 5%. Therefore, the molecular classification by immunohistochemistry is a LUMINAL A, which indicates the possibility of a better prognosis. A few days later, the patient was submitted for a radical mastectomy on the right breast. During the surgery, it was also performed a sentinel lymph nodes (SLN) scintigraphy and analysis of the material collected from the right breast. The conclusion expressed positive screening for malignant cells, two lymph nodes compromised by macrometastasis (large focus measuring 1.2 cm with capsular transposition associated) and positive screening for malignant cells suggestive of carcinoma. The tumor, according to a grading system, presented a Scarff-Bloom Richardson modified by Elston and Ellis grade III, with tubular grade 3, nuclear grade 3, and mitotic index 2. It was also identified as focal tumor necrosis, vascular invasion, and perineural invasion. The pathological staging of the tumor was pT2 pN1a (SN+) pMx.