JOURNAL OF ESTHETIC AND RESTORATIVE DENTISTRY, Issue 1 2002
DOUGLAS H. MAHN DDS
ABSTRACT Esthetic correction of gingival recession is an important goal of periodontal therapy. This article describes a surgical technique that combines a modified tunnel technique and an acellular dermal connective tissue allograft. With the aid of vertical incisions, a tunnel is created under the buccal mucosa of the affected tooth. These incisions enable easy access for graft placement and create mobility for gingival coronal positioning. The use of an acellular dermal connective tissue allograft eliminates the need for a surgical palatal donor site. This minimizes postsurgical complications. CLINICAL SIGNIFICANCE The combination of a modified tunnel technique and an acellular dermal connective tissue allograft permits esthetic root coverage in a manner that reduces postsurgical complications. [source]

Allograft with unrelated donor accentuates the gastrointestinal toxicity associated with high-dose melphalan and total body irradiation preparative for bone marrow transplantation in children

PEDIATRIC TRANSPLANTATION, Issue 4 2000
K. Vettenranta
Abstract: The use of high-dose melphalan ( l -phenyalalanine mustard or l -PAM) has been shown to be associated with both hematological and non-hematological toxicity. It has been employed in the conditioning for allogeneic stem cell transplants from related donors but experience on its use in the unrelated setting has not been reported. As an attempt to elucidate the role of high-dose l -PAM (210 mg/m2) and total body irradiation (TBI) as a preparative regimen for allogeneic marrow transplantation from matched unrelated donors, they were employed in an institutional pilot series of seven pediatric patients. When compared with recipients of unrelated marrow grafts conditioned using other regimens, those treated with high-dose l -PAM experienced a markedly more severe acute graft-vs.-host disease (GvHD). The overall incidence of grade III,IV acute GvHD was higher (86% vs. 14%) among those treated with l -PAM. As judged by gastrointestinal (GI) symptoms, clinically significant (stages ++ to ++++) gut GvHD was strikingly more prevalent among those treated with l -PAM (86% vs. 9%, p<0.005). Toxic mortality prior to day +100 was 29% in the l -PAM group and 9% in the non- l -PAM group of patients. With a mean follow-up of 21 months no increase in the incidence of chronic GvHD has been encountered among those conditioned with l -PAM. We conclude that the use of preparative L -PAM for allogeneic transplants from unrelated donors is associated with considerable procedure-related toxicity. We strongly suggest its use in this setting to be viewed with caution. [source]

REVIEW ARTICLE: Tolerance to the Foetal Allograft?

AMERICAN JOURNAL OF REPRODUCTIVE IMMUNOLOGY, Issue 6 2010
Gérard Chaouat
Citation Chaouat G, Petitbarat M, Dubanchet S, Rahmati M, Ledée N. Tolerance to the Foetal Allograft? Am J Reprod Immunol 2010 In this review, we will detail the concept of tolerance and its history in reproductive immunology. We will then consider whether it applies to the foetal,maternal relationship and discuss the mechanisms involved in non-rejection of the foeto-placental unit. [source]

Evolving Paradigms That Determine the Fate of an Allograft

AMERICAN JOURNAL OF TRANSPLANTATION, Issue 5 2010
J. S. Bromberg
Despite the many advances in both immunological knowledge and the practical application of clinical immunosuppression, the holy grail of indefinite graft survival with immune tolerance in clinical solid organ transplantation remains a distant dream. The tremendous progress made in understanding the molecular and cellular basis of allograft rejection has not been translated into durable modalities that have advanced clinical care and outcomes. Indeed, currently used drugs and treatment protocols, largely directed at inhibiting alloreactive T cells, have not optimally improved allograft survival or function. A shift in emphasis, focusing on under appreciated immune pathways must now be considered to make further improvement. We highlight three areas of recent interest, complement, NK cells and lymphatics, which reinforce the concept that the transplant community must direct attention on how the immune system as a whole responds to a transplant. The current challenge is to integrate molecular, cellular and anatomic concepts to achieve the equivalent of a unified field theory of the immune response to organ transplants. [source]

PD-1/B7-H1 Interaction Contribute to the Spontaneous Acceptance of Mouse Liver Allograft

AMERICAN JOURNAL OF TRANSPLANTATION, Issue 1 2010
M. Morita
The programmed death-1 (PD-1)/B7-H1 pathway acts as an important negative regulator of immune responses. We herein investigated the role of the PD-1/B7-H1 pathway in establishing an immunological spontaneous tolerance status in mouse liver allografting. B7-H1 is highly expressed on the donor-derived tissue cells and it is also associated with the apoptosis of infiltrating T cells in the allografts. Strikingly, a blockade of the PD-1/B7-H1 pathway via anti-B7-H1mAb or using B7-H1 knockout mice as a donor led to severe cell infiltration as well as hemorrhaging and necrosis, thus resulting in mortality within 12 days. Furthermore, the expression of the FasL, perforin, granzyme B, iNOS and OPN mRNA in the liver allografts increased in the antibody-treated group in comparison to the controls. Taken together, these data revealed that the B7-H1 upregulation on the tissue cells of liver allografts thus plays an important role in the apoptosis of infiltrating cells, which might play a critical role of the induction of the spontaneous tolerance after hepatic transplantation in mice. [source]

Strongyloides Stercoralis Hyperinfection Transmitted by Liver Allograft in a Transplant Recipient

AMERICAN JOURNAL OF TRANSPLANTATION, Issue 11 2009
M. J. Rodriguez-Hernandez
We describe a case of Strongyloides stercoralis hyperinfection in a liver allograft recipient 2.5 months after transplantation. The patient lives in Spain, which is not considered an endemic country for strongyloidiasis, and denied prior residence or travel to any known endemic area. The initial symptoms were fever and vomiting, and he subsequently developed a severe respiratory disease. An endoscopic biopsy of ulcerative lesions of the duodenum revealed massive mucosa infiltration by larvae and adult worms, which were also found in respiratory samples. The patient was successfully treated with combined therapy with albendazole and ivermectin. The strongyloides infection was transmitted by the liver allograft. The donor was from Ecuador and, retrospectively, his serum tested positive for S. stercoralis IgG antibodies. Additionally, the pancreas,left kidney allograft recipient from the same donor later developed an intestinal strongyloidiasis without hyperinfection syndrome. To our knowledge, this is the first confirmed case of S. stercoralis infection transmission from the same donor to two solid allograft recipients. [source]

Aspergillus Colonization of the Lung Allograft Is a Risk Factor for Bronchiolitis Obliterans Syndrome

AMERICAN JOURNAL OF TRANSPLANTATION, Issue 8 2009
S. S. Weigt
Multiple infections have been linked with the development of bronchiolitis obliterans syndrome (BOS) post-lung transplantation. Lung allograft airway colonization by Aspergillus species is common among lung transplant recipients. We hypothesized that Aspergillus colonization may promote the development of BOS and may decrease survival post-lung transplantation. We reviewed all lung transplant recipients transplanted in our center between January 2000 and June 2006. Bronchoscopy was performed according to a surveillance protocol and when clinically indicated. Aspergillus colonization was defined as a positive culture from bronchoalveolar lavage or two sputum cultures positive for the same Aspergillus species, in the absence of invasive pulmonary Aspergillosis. We found that Aspergillus colonization was strongly associated with BOS and BOS related mortality in Cox regression analyses. Aspergillus colonization typically preceded the development of BOS by a median of 261 days (95% CI 87,520). Furthermore, in a multivariate Cox regression model, Aspergillus colonization was a distinct risk factor for BOS, independent of acute rejection. These data suggest a potential causative role for Aspergillus colonization in the development of BOS post-lung transplantation and raise the possibility that strategies aimed to prevent Aspergillus colonization may help delay or reduce the incidence of BOS. [source]

Early Renal Ischemia-Reperfusion Injury in Humans Is Dominated by IL-6 Release from the Allograft

AMERICAN JOURNAL OF TRANSPLANTATION, Issue 7 2009
D. K. De Vries
The pathophysiology of ischemia/reperfusion (I/R) injury is complex, and current knowledge of I/R injury in humans is incomplete. In the present study, human living-donor kidney transplantation was used as a highly reproducible model to systematically study various processes potentially involved in early I/R injury. Unique, direct measurements of arteriovenous concentration differences over the kidney revealed massive release of interleukin (IL)-6 in the first 30 minutes of graft reperfusion and a modest release of IL-8. Among the assessed markers of oxidative and nitrosative stress, only 15(S)-8- iso -PGF2, was released. When assessing cell activation, release of prothrombin factor 1 + 2 indicated thrombocyte activation, whereas there was no release of markers for endothelial activation or neutrophil activation. Common complement activation complex sC5b-9 was not released into the bloodstream, but was released into urine rapidly after reperfusion. To investigate whether IL-6 plays a modulating role in I/R injury, a mouse experiment of renal I/R injury was performed. Neutralizing anti-IL-6 antibody treatment considerably worsened kidney function. In conclusion, this study shows that renal I/R in humans is dominated by local IL-6 release. Neutralization of IL-6 in mice resulted in a significant aggravation of renal I/R injury. [source]

Orthotopic, but Reversed Implantation of the Liver Allograft in Situs Inversus Totalis,A Simple New Approach to a Difficult Problem

AMERICAN JOURNAL OF TRANSPLANTATION, Issue 7 2009
S. C. Rayhill
Situs inversus totalis is a rare congenital anomaly in which the heart and abdominal organs are oriented in a mirror image of normal. It provides a unique challenge as there is no established technique for liver transplantation in these patients. Employing two major alterations from our standard technique, a liver was transplanted in the left subphrenic space of a patient with situs inversus totalis. First, the liver was flipped 180° from right to left (facing backward). Second, a reversed cavaplasty (anterior, not posterior, donor suprahepatic caval incision) was performed. Otherwise, it was standard, with end-to-end anastomoses of the portal vein, hepatic artery and bile duct. Three years after the entirely uneventful transplant, the recipient continues to enjoy the benefits of a normally functioning liver. The described technique prevented torsion, kinking and tension on the anastomosed structures by allowing the liver to sit naturally in an anatomical position in the left hepatic fossa. As it required no special measurements or maneuvers, the technique was easy to execute and required no donor liver size restrictions. This novel technique, with a reversed cavaplasty and a 180° right-to-left flip of the liver into a left-sided hepatic fossa, may be ideal for situs inversus totalis. [source]

Airway Epithelial Cell Senescence in the Lung Allograft

AMERICAN JOURNAL OF TRANSPLANTATION, Issue 7 2008
S. M. Parker
Chronic lung allograft dysfunction, manifesting as bronchiolitis obliterans syndrome (BOS), is characterized by airway epithelial injury, impaired epithelial regeneration and subsequent airway remodeling. Increased cellular senescence has been reported in renal and liver allografts affected by chronic allograft dysfunction but the significance of cellular senescence in the airway epithelium of the transplanted lung is unknown. Thirty-four lung transplant recipients, 20 with stable graft function and 14 with BOS, underwent transbronchial lung biopsy and histochemical studies for senescence markers in small airways. Compared to nontransplant control lung tissue (n = 9), lung allografts demonstrate significantly increased airway epithelial staining for senescence-associated beta galactosidase (SA ,-gal) (p = 0.0215), p16ink4a (p = 0.0002) and p21waf1/cip (p = 0.0138) but there was no difference in expression of these markers between stable and BOS affected recipients (p > 0.05). This preliminary cross-sectional study demonstrates that cellular senescence occurs with increased frequency in the airway epithelium of the lung allograft but does not establish any association between airway epithelial senescence and BOS. A prospective longitudinal study is required to better address any potential causal association between airway epithelial senescence in stable allograft recipients and the subsequent development of BOS. [source]

Successful Management of Eviscerated Renal Allograft with Preservation of Function

AMERICAN JOURNAL OF TRANSPLANTATION, Issue 5 2008
H. Jeon
Although most wound complications after renal transplantation are minor, the renal allograft, in its superficial and extraperitoneal location, is vulnerable to exposure if there is wound breakdown resulting in loss of overlying tissue. We describe a 66-year-old man who received a renal allograft from a deceased donor for end-stage renal disease (ESRD) secondary to polycystic kidney disease. His immediate posttransplant course was complicated by delayed graft function from acute tubular necrosis, reexploration for perigraft hematoma and subsequent wound dehiscence. After unsuccessful conservative wound care, the renal allograft became completely eviscerated due to fascial retraction of the dehisced wound. While the allograft was initially covered with a pedicled rectus femoris muscle flap, several local tissue rearrangements were required for definitive coverage. The allograft function was recovered after initial flap coverage and was subsequently maintained; follow-up more than 2 years after transplantation has demonstrated not only continued stable graft function but also complete healing of the dehiscent wound. [source]

Acute Humoral Rejection in Kidney Allograft Following a Third-Party Arterial Transplantation

AMERICAN JOURNAL OF TRANSPLANTATION, Issue 12 2006
S. Ferrari-Lacraz
No abstract is available for this article. [source]

A New Technique for Reconstruction of the Atrophied Narrow Alveolar Crest in the Maxilla Using Morselized Impacted Bone Allograft and Later Placement of Dental Implants

CLINICAL IMPLANT DENTISTRY AND RELATED RESEARCH, Issue 2 2008
Per Holmquist DDS
ABSTRACT Background: In cases when the alveolar crest is too narrow to host an implant, lateral augmentation is required. The use of autogenous bone blocks harvested from the iliac crest is often demanded. One disadvantage is the associated patient morbidity. Purpose: The purpose of this study was to clinically and histologically evaluate the use of morselized impacted bone allograft, a novel technique for reconstruction of the narrow alveolar crest. Materials and Methods: Two patients with completely edentulous maxillae and one partially edentulous, with a mean age of 77 years (range 76,79 years) were included in the study. The alveolar crest width was <3 mm without possibility to place any implant. Bone grafts were taken from a bone bank in Gävle Hospital. Bone from the neck of femur heads was milled to produce bone chips. The milled bone was partially defatted by rinsing in 37°C saline solution. After compression of the graft pieces with a size of 15 mm (height), 30 mm (length), and 6 mm (width), they were then fit to adapt to the buccal surface of the atrophied alveolar crest. One piece was placed to the right and one to the left side of the midline. On both sides fibrin glue was used (Tisseel®, Baxter AG, Vienna, Austria) to stabilize the graft. After 6 months of graft healing, dental implants were placed, simultaneously biopsies were harvested and in one patient two oxidized microimplants were placed. At the time of abutment connection, microimplants were retrieved with surrounding bone for histology. Fixed screw-retained bridges were fabricated in mean of 7 months after implant surgery. Radiographs were taken before and after implant surgery and after 1 year of loading. Results: Sixteen implants with an oxidized surface were placed (TiUnite®, Nobel Biocare AB, Göteborg, Sweden). After 1 year of functional loading, all implants were clinically stable. The marginal bone loss was 1.4 mm (SD 0.3) after 1 year of loading. The histological examination showed resorption and subsequent bone formation on the allograft particles. There were no signs of inflammatory cell infiltration in conjunction with the allograft. The two microimplants showed bone formation directly on the implant surface. Conclusions: This study shows that morselized impacted bone allograft can be used to increase the width of the atrophied narrow alveolar crest as a good alternative to autogenous bone grafts in elderly patients. The histological examination of biopsies revealed a normal incorporation process and no signs of an immunological reaction. Further studies with larger samples are of important to be able to conclude if equal results can be obtained using morselized impacted bone allograft as for autogenous bone graft. [source]

Chondrocyte viability in press-fit cryopreserved osteochondral allografts

JOURNAL OF ORTHOPAEDIC RESEARCH, Issue 4 2004
Madhura D. Gole
Abstract The viability of chondrocytes in press-fit glycerol-preserved osteochondral allografts was compared to that in fresh autografts, after transplantation into load-bearing and non-load-bearing sites in mature sheep stifle joints. We used macroscopic grading, tonometer pen indentation testing, histology, sulfate uptake and viability as determined by confocal-microscopy to assess cartilage condition. Despite there being no statistical differences between macroscopic appearance and tonometer testing of all grafts, confocal microscopy and histology demonstrated a positive effect of load-bearing placement on cryopreserved osteochondral allografts. Allografts transplanted into load-bearing sites demonstrated superior confocal microscopy-measured chondrocyte viability (77% ± 17%SD) than those transplanted into non-load-bearing sites (25%±2%). Load-bearing effect was not seen in autografts (78%±15%), and was comparable in adjacent cartilage (83%±9%). Similarly, load-bearing allografts demonstrated histological scoring closer to that of autografts and adjacent cartilage, all of which fared significantly better than non-load-bearing allografts. Load-bearing allografts had a greater amount of fibrocartilage than autografts or adjacent cartilage but less fibrocartilage than non-load-bearing allografts. Both autografts and allografts had non-significant increases in metabolism compared to adjacent cartilage as measured by sulfate-uptake. Load-bearing placement improved chondrocyte viability of glycerol cryopreserved osteochondral allograft following a press-fit implantation. Published by Elsevier Ltd. All on behalf of orthopaedic Research Society. [source]

R2: Identification of renal potential progenitor/stem cells that participate in the renal regeneration processes of kidney allograft fibrosis

NEPHROLOGY, Issue 6 2008
JI BAO
SUMMARY: Aim: Many strategies are explored to ameliorate kidney allograft tubular atrophy and interstitial fibrosis (TA/IF), but little progress has been achieved. The latest evidence suggested that CD133+ cell in kidney represent a potential multipotent adult resident stem cell population that may contribute to the renal injury repair. Here we investigate whether the CD133+ cells exist in transplanted renal and exert a growth and self-repair procedure in TA/IF. Methods: Allografts from rat kidney transplant models were harvested at 4 weeks, 8 weeks and 12 weeks post transplantation. We performed immunohistochemistry to detect the CD133+ cells and immunofluorescence to detect the co-expression of CD133 or Pax-2 with Ki-67. We furthermore analysed the E-cadherin using serial sections. Results: CD133+ cells were seldom seen in control kidney, but distributed sporadically in the cortex parenchyma along with the deterioration of TA/IF. The number of CD133+ cell increased after 4 weeks and reached the peak at 8 weeks, then decreased at 12 weeks. From 8 weeks, some new tubules expressing E-cadherin were constructed with CD133+ cells. Almost all the CD133+ cells were Ki-67-positive, but not all the Ki-67+ cells expressed CD133. The rest Ki-67+ cells almost expressed Pax-2. Conclusion: Our study reveals that when majority of the tubules are damaged, a self-repair mechanism is evoked by potential adult stem cells to compensate the renal function. Thus, potential adult resident stem cells offer a new avenue for autologous cell therapies in TA/IF. [source]

Features of chronic allograft rejection on rat small intestine transplantation

PEDIATRIC TRANSPLANTATION, Issue 2 2007
Hao Ma
Abstract:, The aim of this study was to develop a model of chronic rejection of the entire small intestine transplantation and to analyze the features of chronic rejection. Allogenic small bowel transplantation was performed in a rat combination of Lewis to F344. Intestines were procured at the 60th and the 90th day after operation. We compared the semiquantitative score of histological parameters. The immunological components involved in the chronic rejection process were evaluated by immunohistochemical staining and the cytokine levels in grafts. The significant characteristics of the allograft on histology were changes of villous architecture, interstitial fibrosis, leukocyte infiltration, and obliterative arteriopathy. Allografts on the 60th day post-transplantation had more score in inflammatory events, while the grafts on the 90th day after operation had more values in ischemia/fibrotic events. The number of infiltrating CD4, CD8 and macrophage cells in allografts progressively decreased over time. The level of intrgraft cytokines such as IL-6, TNF- , and IL-10 in the 90th day after transplantation also decreased compared with that in the 60th day. These data suggested that in the early stage (POD 60), there were more active and intense inflammatory events; later (POD 90) allografts manifested less inflammation and more arterial obliteration and fibrosis. [source]

Pretreatment With Portal Venous Ultraviolet B Irradiated Donor Alloantigen Promotes Donor-Specific Tolerance to Rat Nerve Allografts,

THE LARYNGOSCOPE, Issue 3 2001
Eric M. Genden MD
Abstract Objective To determine if a single intraportal inoculation of ultraviolet B-irradiated (UVB) donor splenocytes can prevent nerve allograft rejection and confer donor-specific immunotolerance to rat nerve allograft segments. Methods Age-matched, class I and class II major histocompatibility complex (MHC) mismatched Buffalo (RT1b) rats were transplanted with a syngeneic nerve isograft, a Lewis (RT1l) nerve allograft, or a Brown-Norway (RT1n) rat nerve allograft segment. Control Buffalo rats in group I received a 3.0-cm Lewis (RT11) sciatic-posterior tibial interposition nerve allograft without pretreatment;group II Buffalo rats received a syngeneic Buffalo nerve isograft without pretreatment. Group III Buffalo recipients were inoculated with 2.5 × 107 UVB-irradiated Lewis donor splenocyte cells by portal venous administration 7 days before transplantation with a 3.0-cm sciatic-posterior tibial nerve allograft from a Lewis (RT11) or a third party Brown-Norway rat (RT1n) donor (group IV). Nerve graft regeneration was assessed with walking track analysis, nerve conduction studies, retrograde neural tracing, nerve graft histology, and morphometry. Recipient immune tolerance was assessed through in vitro immunological assessment. Results Pretreatment with UVB-irradiated donor splenocytes 7 days before transplantation prevented nerve allograft rejection. Pretreated animals receiving a nerve allograft recovered limb function, and demonstrated morphological, histological, and electrophysiologic parameters of nerve regeneration similar to that measured in rats receiving a nerve isograft. In vitro immunological assessment by mixed lymphocyte culture (MLC), cytotoxic T lymphocyte (CTL) assay, limiting dilution analysis (LDA) of helper (pTH) and cytotoxic (pCTL) precursor frequencies, and IL-2 production demonstrated a marked donor-specific suppression in allografted animals pretreated with intraportal UVB-irradiated donor splenocytes. These assessments correlated with indefinite acceptance of donor nerve allografts. Conclusions A single pretreatment with a single intraportal dose of UVB-modified donor antigen specifically induces tolerance to peripheral nerve allografts in rats. [source]

Case Report: Fatal Apophysomyces elegans Infection Transmitted by Deceased Donor Renal Allografts

AMERICAN JOURNAL OF TRANSPLANTATION, Issue 9 2010
B. D. Alexander
Two patients developed renal mucormycosis following transplantation of kidneys from the same donor, a near-drowning victim in a motor vehicle crash. Genotypically, indistinguishable strains of Apophysomyces elegans were recovered from both recipients. We investigated the source of the infection including review of medical records, environmental sampling at possible locations of contamination and query for additional cases at other centers. Histopathology of the explanted kidneys revealed extensive vascular invasion by aseptate, fungal hyphae with relative sparing of the renal capsules suggesting a vascular route of contamination. Disseminated infection in the donor could not be definitively established. A. elegans was not recovered from the same lots of reagents used for organ recovery or environmental samples and no other organ transplant-related cases were identified. This investigation suggests either isolated contamination of the organs during recovery or undiagnosed disseminated donor infection following a near-drowning event. Although no changes to current organ recovery or transplant procedures are recommended, public health officials and transplant physicians should consider the possibility of mucormycosis transmitted via organs in the future, particularly for near-drowning events. Attention to aseptic technique during organ recovery and processing is re-emphasized. [source]

Successful Salvage of Kidney Allografts Threatened by Ureteral Stricture Using Pyelovesical Bypass

AMERICAN JOURNAL OF TRANSPLANTATION, Issue 6 2010
R. A. Azhar
Ureteral stricture is the most common urologic complication after renal transplantation. When endourologic management fails, open ureteral reconstruction remains the standard treatment. The complexity of some of these procedures makes it necessary to explore other means of repair. This study evaluated the intermediate-term outcome of subcutaneous pyelovesical bypass graft (SPBG) on renal transplant recipients. We reviewed 8 patients (6 male and 2 female; mean age 52 years) with refractory ureteral strictures postrenal transplantation, who received SPBG as salvage therapy. All patients failed endourologic management and half failed open management of their strictures. After a mean follow-up of 19.4 months, 7 out of 8 renal grafts have good function with mean GFR of 58.5 mL/min/1.73 m2, without evidence of obstruction or infection. One patient lost his graft due to persistent infection of the SPBG and one patient developed a recurrent urinary tract infection managed with long-term antibiotics. SPBG offers a last resort in the treatment of ureteral stricture after renal transplantation refractory to conventional therapy. [source]

Recent Progress and New Perspectives in Studying T Cell Responses to Allografts

AMERICAN JOURNAL OF TRANSPLANTATION, Issue 5 2010
A. Valujskikh
Studies in the past decade advanced our understanding of the development, execution and regulation of T-cell-mediated allograft rejection. This review outlines recent progress and focuses on three major areas of investigation that are likely to guide the development of graft-prolonging therapies in the future. The discussed topics include the contribution of recently discovered molecules to the activation and functions of alloreactive T cells, the emerging problem of alloreactive memory T cells and recently gained insights into the old question of transplantation tolerance. [source]

Alternative Macrophage Activation-Associated Transcripts in T-Cell-Mediated Rejection of Mouse Kidney Allografts

AMERICAN JOURNAL OF TRANSPLANTATION, Issue 3 2010
K. S. Famulski
Macrophages display two activation states that are considered mutually exclusive: classical macrophage activation (CMA), inducible by IFNG, and alternative macrophage activation (AMA), inducible by IL4 and IL13. CMA is prominent in allograft rejection and AMA is associated with tissue remodeling after injury. We studied expression of AMA markers in mouse kidney allografts and in kidneys with acute tubular necrosis (ATN). In rejecting allografts, unlike interferon gamma (IFNG) effects and T-cell infiltration that developed rapidly and plateaued by day 7, AMA transcripts (Arg1, Mrc1, Mmp12 and Ear1) rose progressively as tubulitis and parenchymal deterioration developed at days 21 and 42, despite persistent IFNG effects. AMA in allografts was associated with transcripts for AMA inducers IL4, IL13 and inhibin A, but also occurred when hosts lacked IL4/IL13 receptors, suggesting a role for inhibin A. Kidneys with ATN injured by ischemia/reperfusion also had increased expression of AMA markers and inhibin A. Thus kidneys undergoing T-cell-mediated rejection progressively acquire macrophages with alternative activation phenotype despite strong local IFNG effects, independent of IL4 and IL13. Although the mechanisms and causal relationships remain to be determined, high AMA transcript levels in rejecting allografts are strongly associated with and may be a consequence of parenchymal deterioration similar to ATN. [source]

Role of TNF, in Early Chemokine Production and Leukocyte Infiltration into Heart Allografts

AMERICAN JOURNAL OF TRANSPLANTATION, Issue 1 2010
D. Ishii
The acute phase cytokines IL-1,, IL-6 and TNF, are produced early during inflammatory processes, including ischemia-reperfusion. The appearance and role of these cytokines in the early inflammation following reperfusion of grafts remain poorly defined. This study investigated the role of TNF, in the induction of early leukocyte infiltration into vascularized heart allografts. TNF, and IL-6 mRNA levels reached an initial peak 3 h posttransplant and a second peak at 9,12 h with equivalent levels in iso- and allografts. A single dose of anti-TNF, mAb given at reperfusion decreased neutrophil and macrophage chemoattractant levels and early neutrophil, macrophage and memory CD8 T-cell infiltration into allografts. Anti-TNF, mAb also extended graft survival from 8.6 ± 0.6 days to 14.1 ± 0.8 days. When assessed on day 7 posttransplant, the number of donor-reactive CD8 T cells producing IFN-, in the spleen was reduced almost 70% in recipients treated with anti-TNF, mAb. Whereas anti-CD154 mAb prolonged survival to day 21, administration of anti-TNF, and anti-CD154 mAb delayed rejection to day 32 and resulted in long-term (>80 days) survival of 40% of the heart allografts. These data implicate TNF, as an important mediator of early inflammatory events in allografts that undermine graft survival. [source]

Localization, Etiology and Impact of Calcium Phosphate Deposits in Renal Allografts

AMERICAN JOURNAL OF TRANSPLANTATION, Issue 11 2009
P. Evenepoel
Hypercalcemia, hypophosphatemia and renal phosphate wasting are common after kidney transplantation. Animal data suggest that these alterations in mineral metabolism may contribute to calcium phosphate (CaPhos) deposition in the kidney and renal dysfunction. We tested the hypothesis that CaPhos deposition is highly prevalent in the early posttransplant period and is related to a disturbed mineral metabolism. For this purpose, biomarkers of mineral metabolism and renal calcium and phosphorus handling were prospectively assessed in 201 renal transplant recipients. CaPhos deposits were observed in 4.6, 30.4 and 24.7% of protocol biopsies obtained at the time of engraftment, and 3 and 12 months thereafter, respectively. In multivariate logistic regression analysis, high calcium and low serum phosphorus levels were independently associated with renal CaPhos deposition at month 3. The extent of CaPhos deposition correlated significantly with the severity of mineral metabolism disturbances. Renal function after a mean follow-up of 33 months was similar in patients with and without CaPhos deposition at month 3. In conclusion, our data demonstrate that CaPhos deposition is highly prevalent in the early posttransplant period and suggest that a disordered mineral metabolism is implicated in its pathogenesis. The clinical relevance of CaPhos deposition remains to be established. [source]

An Anti-CD103 Immunotoxin Promotes Long-Term Survival of Pancreatic Islet Allografts

AMERICAN JOURNAL OF TRANSPLANTATION, Issue 9 2009
L. Zhang
Previous studies using knockout mice document a key role for the integrin CD103 in promoting organ allograft rejection and graft-versus-host disease. However, a determination of whether blockade of the CD103 pathway represents a viable therapeutic strategy for intervention in these processes has proven problematic due to the lack of reagents that efficiently deplete CD103+ cells from wild type hosts. To circumvent this problem, we conjugated the nondepleting anti-CD103 monoclonal antibody, M290, to the toxin, saporin, to produce an immunotoxin (M290-SAP) that efficiently depletes CD103+ cells in vivo. Herein, we show that M290-SAP dramatically reduces the frequency and absolute numbers of CD103-expressing leukocytes in the blood, spleen, mesenteric lymph nodes and intestinal epithelium of treated mice. We further demonstrate that M290-SAP promotes indefinite islet allograft survival in a fully MHC mismatched mouse model. The prolonged islet allograft survival resulting from M290-SAP treatment was associated with multiple effects in the host immune system including not only depletion of CD103-expressing leukocytes, but also an increase in CD4+CD25+FoxP3+ T regulatory cells and a predominance of effector-memory CD8 T cells. Regardless of the underlying mechanisms, these data document that depletion of CD103-expressing cells represents a viable strategy for therapeutic intervention in allograft rejection. [source]

Scoring Total Inflammation Is Superior to the Current Banff Inflammation Score in Predicting Outcome and the Degree of Molecular Disturbance in Renal Allografts

AMERICAN JOURNAL OF TRANSPLANTATION, Issue 8 2009
M. Mengel
Emerging molecular analysis can be used as an objective and independent assessment of histopathological scoring systems. We compared the existing Banff i-score to the total inflammation (total i-) score for assessing the molecular phenotype in 129 renal allograft biopsies for cause. The total i-score showed stronger correlations with microarray-based gene sets representing major biological processes during allograft rejection. Receiver operating characteristic curves showed that total-i was superior (areas under the curves 0.85 vs. 0.73 for Banff i-score, p = 0.012) at assessing an abnormal cytotoxic T-cell burden, because it identified molecular disturbances in biopsies with advanced scarring. The total-i score was also a better predictor of graft survival than the Banff i-score and essentially all current diagnostic Banff categories. The exception was antibody-mediated rejection which is able to predict graft loss with greater specificity (96%) but at low sensitivity (38%) due to the fact that it only applies to cases with this diagnosis. The total i-score is able to achieve moderate sensitivities (60,80%) with losses in specificity (60,80%) across the whole population. Thus, the total i-score is superior to the current Banff i-score and most diagnostic Banff categories in predicting outcome and assessing the molecular phenotype of renal allografts. [source]

Purified Eicosapentaenoic Acid Induces Prolonged Survival of Cardiac Allografts and Generates Regulatory T Cells

AMERICAN JOURNAL OF TRANSPLANTATION, Issue 6 2009
D. Iwami
Fish oil, which is rich in eicosapentaenoic acid (EPA), has been found to have immunomodulatory effects. We examined whether administration of purified EPA affected survival of fully mismatched murine cardiac allografts. Hearts from C57BL/10 (H-2b) mice were transplanted into CBA (H-2k) recipients treated with one intraperitoneal dose of purified EPA the day of transplantation. Untreated CBA recipients and recipients given 0.1 g/kg of EPA rejected C57BL/10 hearts (median survival time [MST], 8 and 13 days, respectively). With a 1.0 g/kg dose of EPA, graft survival was markedly prolonged (MST >100 days). To determine whether regulatory cells were generated, naïve mice (secondary recipients) underwent adoptive transfer of splenocytes from EPA-treated primary recipients and cardiac allograft transplantation. Adoptive transfer of whole, CD4+ and CD4+CD25+ splenocytes from EPA-treated recipients induced indefinite survival in secondary recipients. Flow cytometry showed that the CD4+CD25+ cells were Foxp3+. In reverse transcriptase-polymerase chain reaction (RT-PCR) studies, the expression of peroxisome proliferator-activated receptor , (PPAR,) mRNA was upregulated by EPA treatment. A PPAR, antagonist abrogated the prolongation of graft survival induced by EPA treatment (MST, 13 days). Thus, in our model, purified EPA induced prolonged survival of fully mismatched cardiac allografts and generated regulatory T cells dependent on PPAR, activation. [source]

Focal C4d+ in Renal Allografts Is Associated with the Presence of Donor-Specific Antibodies and Decreased Allograft Survival

AMERICAN JOURNAL OF TRANSPLANTATION, Issue 4 2009
R. L. Kedainis
Diffuse peritubular capillary C4d deposition in renal allograft biopsies is associated with donor-specific antibodies (DSA) and graft failure. The significance of focal C4d+ is unclear. We reviewed 368 biopsies from 301 patients performed for renal dysfunction or proteinuria over 5 years. Diffuse C4d+, focal C4d+ and C4d- detected by immunofluorescence occurred in 9.5%, 20.9% and 69.4% of biopsies, respectively. Patients were similar in gender, age, cause of renal disease, donor source, HLA mismatch, serum creatinine at baseline and interval from transplantation to biopsy. Diffuse and focal C4d+ were associated with acute cellular rejection (p < 0.001). Transplant glomerulopathy was associated with diffuse C4d+. DSA at the time of biopsy, were positive in 79.3% of diffusely C4d+ patients, 68.8% of those with focal C4d+ (p = 0.27) and 9.9% of patients with C4d- (p < 0.001, compared to either the focal or diffuse groups, respectively). Allograft survival at 40 months was lower in diffuse C4d+ compared to the C4d- group (p = 0.014), but not when compared to the focal C4d+ group. There was a clear trend toward worse graft survival in patients with focal C4d+ in this time interval, but focal C4d+ compared to both diffuse C4d+ and C4d-groups was not statistically significant (p = 0.08). [source]

The Early Course of Kidney Allograft Rejection: Defining the Time When Rejection Begins

AMERICAN JOURNAL OF TRANSPLANTATION, Issue 3 2009
G. Einecke
We studied the early events in mouse kidney allografts and isografts to define when allorecognition begins and when alloimmune tissue injury begins. Allografts but not isografts showed T-cell infiltration in perivascular areas from day 1, but tubulitis and arteritis did not develop until day 7. Flow cytometry confirmed the early allospecific CD3+CD8+ T-cell infiltrate. At day 1, both allografts and isografts showed extensive transcriptome changes, reflecting the response to surgery, but only allografts showed expression of interferon-gamma (IFN-,)-inducible transcripts and T-cell-associated transcripts. Although the number of CD68+ myeloid cell numbers did not increase in day 1 isografts or allografts, mRNA expression for myeloid markers was increased in isografts and allografts, suggesting activation of resident cells of the macrophage-dendritic cell series (MMDCs) in response to injury, followed by increased CD68+ cell numbers from day 2. By day 3, an interstitial T-cell and MMDC infiltrate was established in allografts, corresponding with the emergence of allospecific tissue injury, as reflected by decreased parenchymal transcripts. Thus, in renal allografts, allorecognition by T cells occurs in perivascular sites by day 1, but alloimmune parenchymal damage begins at day 3, coinciding with the emergence of the interstitial T-cell,MMDC infiltrate. [source]

Renal Allografts with IF/TA Display Distinct Expression Profiles of Metzincins and Related Genes

AMERICAN JOURNAL OF TRANSPLANTATION, Issue 3 2009
S. Rödder
Chronic renal allograft injury is often reflected by interstitial fibrosis (IF) and tubular atrophy (TA) without evidence of specific etiology. In most instances, IF/TA remains an irreversible disorder, representing a major cause of long-term allograft loss. As members of the protease family metzincins and functionally related genes are involved in fibrotic and sclerotic processes of the extracellular matrix (ECM), we hypothesized their deregulation in IF/TA. Gene expression and protein level analyses using allograft biopsies with and without Banff'05 classified IF/TA illustrated their deregulation. Expression profiles of these genes differentiated IF/TA from Banff'05 classified Normal biopsies in three independent microarray studies and demonstrated histological progression of IF/TA I to III. Significant upregulation of matrix metalloprotease-7 (MMP-7) and thrombospondin-2 (THBS-2) in IF/TA biopsies and sera was revealed in two independent patient sets. Furthermore, elevated THBS-2, osteopontin (SPP1) and ,-catenin may play regulatory roles on MMP. Our findings further suggest that deregulated ECM remodeling and possibly epithelial to mesenchymal transition (EMT) are implicated in IF/TA of kidney transplants, and that metzincins and related genes play an important role in these processes. Profiling of these genes may be used to complement IF/TA diagnosis and to disclose IF/TA progression in kidney transplant recipients. [source]

Potential Role of NKG2D and Its Ligands in Organ Transplantation: New Target for Immunointervention

AMERICAN JOURNAL OF TRANSPLANTATION, Issue 2 2009
B. Suárez-Álvarez
NKG2D is one of the best characterized activating receptors on Natural Killer (NK) and CD8+ T cells. This receptor recognizes several different ligands (MICA/MICB and ULBPs) induced by cellular stress and infection. In addition to the role described in cancer surveillance, recent data highlight the importance of NKG2D and its ligands in organ transplantation. Allografts show evidence of MICA and MICB expression in both acute and chronic rejection. The presence of anti-MICA antibodies has been correlated with incidence of graft rejection. Furthermore, NKG2D-ligand engagement activates NK cells, which provides T-cell costimulation, and enhances antigen specific CTL-mediated cytotoxicity. Activated NK cells may function as a bridge between innate and adaptive immunity associated with transplantation. Activated NK cells in response to IL-15 can also trigger organ rejection through NKG2D and affect the maturation of both donor and recipient antigen presenting cells (APCs) and ultimately the T-cell allogeneic response. Regulatory T cells, which modulate T-cell responses in organ transplantation and infections, were reduced in numbers by NK cells exposed to intracellular pathogens, possibly via interaction with one NK2GD receptor. Blockage of NKG2D-NKG2D-L interactions provides a novel pathway for development of inhibitors. These studies have important clinical and therapeutic implications in solid organ transplantation. [source]