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1.
Lab Med ; 55(2): 245-248, 2024 Mar 07.
Article in English | MEDLINE | ID: mdl-37294932

ABSTRACT

BACKGROUND: Double trisomies are rare findings among products of conception and are often lethal to the developing embryo or fetus. METHODS: Here we describe a double trisomy case with symptoms of threatened miscarriage at 9 weeks gestation. Ultrasound revealed an anembryonic pregnancy. Pregnancy was terminated by dilation and curettage at gestational age 11 weeks and 6 days. Histologic examination and chromosome microarray were performed on a formalin-fixed product of conception (POC) sample to identify the cause of the anembryonic pregnancy. RESULTS: Chromosome microarray analysis revealed a female chromosome complement with double trisomies 10 and 20, arr(10,20)x3, consistent with a karyotype of 48,XX,+10,+20. CONCLUSION: To the best of our knowledge, this is the first reported case of double trisomy 10 and 20 in a POC. Due to nonspecific histopathological findings, chromosomal microarray is a powerful tool in identifying and differentiating chromosomal aneuploidies.


Subject(s)
Abortion, Spontaneous , Chromosome Disorders , Pregnancy , Female , Humans , Infant , Trisomy/diagnosis , Trisomy/genetics , Chromosome Aberrations , Chromosome Disorders/diagnosis , Chromosome Disorders/genetics , Aneuploidy , Karyotyping , Abortion, Spontaneous/genetics , Abortion, Spontaneous/pathology
2.
Lab Med ; 55(1): 103-105, 2024 Jan 06.
Article in English | MEDLINE | ID: mdl-37184333

ABSTRACT

Triploidy is a genetic occurrence in which the chromosome count is 3n = 69 with a double (2n) chromosomal contribution to the conceptus from one parent. Such pregnancies are usually nonviable and are estimated to account for approximately 1% of recognized conceptions and 10% of recognized miscarriages. Majority opinion is that fetal losses due to triploidies are caused by the presence of 2 copies of paternal chromosomes. In this study, we present a digynic monoandric triploid miscarriage from a 32-year-old G7P1051 at approximately 13 weeks gestation, in which 2 copies of the maternal chromosomes are present in the fetus. This unusual phenomenon is supported by nonmolar placental histology, chromosomal microarray, and short tandem repeat assays, with the latter 2 being discussed in detail. Furthermore, this study includes discussion of recurrent miscarriage, recurrent triploidy, and long-term clinical follow-up of the patient.


Subject(s)
Abortion, Habitual , Triploidy , Humans , Pregnancy , Female , Adult , Placenta , Abortion, Habitual/genetics
3.
Nat Commun ; 14(1): 5603, 2023 09 12.
Article in English | MEDLINE | ID: mdl-37699929

ABSTRACT

Lassa virus is a member of the Arenaviridae family, which causes human infections ranging from asymptomatic to severe hemorrhagic disease with a high case fatality rate. We have designed and generated lipid nanoparticle encapsulated, modified mRNA vaccines that encode for the wild-type Lassa virus strain Josiah glycoprotein complex or the prefusion stabilized conformation of the Lassa virus glycoprotein complex. Hartley guinea pigs were vaccinated with two 10 µg doses, 28 days apart, of either construct. Vaccination induced strong binding antibody responses, specific to the prefusion conformation of glycoprotein complex, which were significantly higher in the prefusion stabilized glycoprotein complex construct group and displayed strong Fc-mediated effects. However, Lassa virus-neutralizing antibody activity was detected in some but not all animals. Following the challenge with a lethal dose of the Lassa virus, all vaccinated animals were protected from death and severe disease. Although the definitive mechanism of protection is still unknown, and assessment of the cell-mediated immune response was not investigated in this study, these data demonstrate the promise of mRNA as a vaccine platform against the Lassa virus and that protection against Lassa virus can be achieved in the absence of virus-neutralizing antibodies.


Subject(s)
Arenaviridae , Lassa virus , Humans , Guinea Pigs , Animals , Lassa virus/genetics , Antibodies, Neutralizing , mRNA Vaccines , Glycoproteins
4.
ACG Case Rep J ; 10(7): e01096, 2023 Jul.
Article in English | MEDLINE | ID: mdl-37501937

ABSTRACT

Proximal esophageal adenocarcinoma is extremely rare. A gastric inlet patch is a lesion of ectopic gastric mucosa usually found in the cervical esophagus and is considered an incidental finding, but there is a risk for malignant transformation. We report the case of a 50-year-old male with gastroesophageal reflux disease with a 6-month history of progressive dysphagia and 20-pound weight loss. Upper endoscopy showed a malignant stricture with adjacent gastric inlet patch. Biopsies obtained from endoscopic ultrasonography showed adenocarcinoma. This case re-emphasizes careful examination of ectopic gastric mucosa and to consider biopsy if there is suspicion for malignant transformation.

5.
Cureus ; 15(5): e38577, 2023 May.
Article in English | MEDLINE | ID: mdl-37284353

ABSTRACT

A 58-year-old African American male was referred for endoscopic evaluation due to a persistent nine-year history of reflux. Previous endoscopy nine years ago revealed a small hiatal hernia and chronic gastritis caused by Helicobacter pylori (H. pylori), which was treated with triple therapy. During the current endoscopic evaluation, findings consistent with reflux esophagitis were identified, along with the discovery of an incidental 6 mm sessile polyp in the gastric fundus. Pathological examination revealed the presence of an oxyntic gland adenoma (OGA). Otherwise, the stomach was found to be unremarkable endoscopically and histologically. OGA is a rare gastric neoplasm that is primarily observed in Japan, with very few reported cases in North America. Studies have suggested a potential association with antacids, while the role of H. pylori in the development of OGA remains controversial. Our patient's OGA was completely resected during the endoscopy, with no recurrence noted on the three-month follow-up.

7.
Case Rep Obstet Gynecol ; 2015: 348279, 2015.
Article in English | MEDLINE | ID: mdl-26417466

ABSTRACT

Fetomaternal hemorrhage (FMH) can be associated with significant perinatal mortality. Our review of the literature did not identify any cases of FMH following placement of an intrauterine pressure catheter (IUPC). In our case, an IUPC was inserted in a patient undergoing induction of labor at term. Fetal bradycardia ensued shortly after placement, warranting an emergent cesarean delivery. Severe neonatal anemia was identified, and evaluation of maternal blood was consistent with massive FMH. This is the first reported association between FMH and IUPC placement. If this relationship is validated in future reports, appropriate changes in clinical practice may be warranted.

9.
J Reprod Med ; 59(11-12): 599-602, 2014.
Article in English | MEDLINE | ID: mdl-25552135

ABSTRACT

BACKGROUND: Coexistence of complete mole and a live fetus is uncommon (1:22,000-100,000), more so with euploidy. CASE: We present a case of a molar pregnancy with a euploid fetus who had close fetal evaluation for second trimester bleeding. The patient presented at 29 weeks' pregnancy with decreased fetal movements, a result of fetomaternal hemorrhage. She underwent cesarean section and delivered a live infant. By close follow-up and a multidisciplinary approach, the appropriate diagnosis and a favorable outcome were achieved. Both mother and the child at 5 years of age are doing well. CONCLUSION: Detailed anatomic and molecular studies demonstrated a complete mole resulting from confined placental mosaicism, with molar tissue showing a single paternal allele at 8/8 informative loci, all shared with the fetus, thus this coexistent molar pregnancy was not that of a separate conceptus.


Subject(s)
Fetomaternal Transfusion/pathology , Hydatidiform Mole/pathology , Placenta/pathology , Female , Humans , Infant, Newborn , Pregnancy
10.
Pediatr Dev Pathol ; 16(5): 327-30, 2013.
Article in English | MEDLINE | ID: mdl-23815756

ABSTRACT

Placentas have been often considered medical waste in hospitals. This view is particularly held by the patients themselves, who may not understand the importance of placental examination. Hospitals have been receiving requests for placental release to patients and need to be prepared to handle these requests. Therefore, a survey was conducted to explore the experiences and practices of perinatal pathologists with respect to placental release. Utilizing SurveyMonkey, we emailed a survey to 192 practicing perinatal pathologists in the United States and Canada. Questions were asked about policies in force at their particular institution, conditions of release, and the purpose of release, ie, what the disposition of the placenta was after release to the family. Thirty-six responses were received; 22 (61.1%) of respondents did allow release of placentas, and those who did not release usually reported that they had not received requests for release. In most cases, specific policies were in place, with multiple departments within the hospital having input on the creation of the policy. Parental signature was required in most cases. The most common reason for patient request was to bury the placenta, although some placental release was for consumption and/or encapsulation. Although there are no specific religious requirements for use or burial of the placenta after delivery, there are many cultural reasons for requests. Hospitals and specific providers need to be aware of this interest and have a specific policy in place so that they are prepared when a request is received.


Subject(s)
Medical Waste Disposal , Pathology, Clinical , Placenta , Practice Patterns, Physicians' , Canada , Female , Humans , Medical Waste Disposal/legislation & jurisprudence , Medical Waste Disposal/standards , Pathology, Clinical/legislation & jurisprudence , Pathology, Clinical/standards , Pregnancy , Surveys and Questionnaires , United States
12.
J Mol Diagn ; 15(4): 466-72, 2013 Jul.
Article in English | MEDLINE | ID: mdl-23665195

ABSTRACT

Array comparative hybridization has been used successfully to identify genomic alterations in stillbirth material; however, high DNA quantity and quality requirements may limit its utility in some fetal samples. Molecular inversion probe (MIP) array analysis of FFPE stillbirth autopsy samples circumvents the challenges associated with karyotype and short-term fetal cell culture, requires limited DNA input, and allows for retrospective evaluation of fetal loss. We performed MIP analysis on archival FFPE autopsy tissue to identify underlying genetic abnormalities not previously detected using traditional cytogenetic methods. Archival FFPE stillbirth cases (≥20 weeks gestation) were identified with the following characteristics: i) the phenotype suggested underlying genomic alterations; ii) the karyotype was either normal or not available and there were no other known genetic abnormalities; or iii) previous microarray testing was not performed. Genomic DNA (75 ng) was processed onto a 330,000-feature MIP array. Twenty-seven of 29 (93.1%) FFPE samples had passing MIP quality control scores. Abnormalities were seen in 3 of 27 (11%) archival samples (deletion of 17q12, trisomy 18, and a case of 4qter duplication and 13qter deletion arising from an unbalanced 4q;13q translocation), which, if identified at the time of autopsy, may have changed the course of medical management. This study highlights the benefits of using MIP array analysis for identification of genomic alterations in FFPE stillbirth autopsy tissue.


Subject(s)
Chromosome Aberrations , DNA/genetics , Oligonucleotide Array Sequence Analysis , Stillbirth/genetics , Comparative Genomic Hybridization , Female , Formaldehyde , Humans , Karyotyping , Molecular Probes , Paraffin Embedding , Pregnancy , Retrospective Studies , Tissue Fixation
13.
Arch Pathol Lab Med ; 137(1): 55-63, 2013 Jan.
Article in English | MEDLINE | ID: mdl-23276175

ABSTRACT

CONTEXT: Molecular genotyping by analysis of DNA microsatellites, also known as short tandem repeats (STRs), is an established method for diagnosing and classifying hydatidiform mole. Distinction of both complete hydatidiform mole and partial hydatidiform mole from nonmolar specimens is relevant for clinical management owing to differences in risk for persistent gestational trophoblastic disease. OBJECTIVE: To determine the technical performance of microsatellite genotyping by using a commercially available multiplex assay, and to describe the application of additional methods to confirm other genetic abnormalities detected by the genotyping assay. DESIGN: Microsatellite genotyping data on 102 cases referred for molar pregnancy testing are presented. A separate panel of mini STR markers, flow cytometry, fluorescence in situ hybridization, and p57 immunohistochemistry were used to characterize cases with other incidental genetic abnormalities. RESULTS: Forty-eight cases were classified as hydatidiform mole (31, complete hydatidiform mole; 17, partial hydatidiform mole). Genotyping also revealed 11 cases of suspected trisomy and 1 case of androgenetic/biparental mosaicism. Trisomy for selected chromosomes (13, 16, 18, and 21) was confirmed in all cases by using a panel of mini STR markers. CONCLUSIONS: This series illustrates the utility of microsatellite genotyping as a stand-alone method for accurate classification of hydatidiform mole. Other genetic abnormalities may be detected by genotyping; confirmation of the suspected abnormality requires additional testing.


Subject(s)
Genotyping Techniques/methods , Hydatidiform Mole/diagnosis , Hydatidiform Mole/genetics , Microsatellite Repeats , Uterine Neoplasms/diagnosis , Uterine Neoplasms/genetics , Bacteria , Female , Flow Cytometry , Humans , Hydatidiform Mole/classification , Immunohistochemistry , In Situ Hybridization, Fluorescence , Male , Mosaicism , Pregnancy , Staining and Labeling , Trisomy , Uterine Neoplasms/classification
15.
Pediatr Dev Pathol ; 14(6): 431-7, 2011.
Article in English | MEDLINE | ID: mdl-21711209

ABSTRACT

This study was undertaken to determine the prevalence of cervical ribs in stillborn fetuses undergoing autopsy at our institution and to search for significant associations with cervical ribs. European studies have reported an increased prevalence of cervical ribs in patients with childhood cancer and in stillborn fetuses. We reviewed data from autopsies performed at Primary Children's Medical Center, Utah, between 2006 and 2009 on 225 stillborns (≥20 weeks) and 93 deceased live-born infants (<1 year). Digital fetal radiographs in anterior-posterior and lateral views had been taken of each subject. Chi-square analysis and general linear models were used for statistical analysis of the data. The overall prevalence of cervical ribs was higher in stillborns than in live-borns who died in the first year (43.1% vs 11.8%). Karyotypes were available for 93 (41.3%) of the stillborns. Of those, cervical ribs were present in 33 of 76 (43.4%) stillborns with normal karyotype and in 13 of 17 (76.4%) stillborns with aneuploidy. Females with unavailable karyotypes were more likely to have cervical ribs than those with normal karyotypes (P  =  0.0002). This greater likelihood was not observed in males. Among the stillborns with normal karyotypes, we found no statistically significant association with gender or gestational age at fetal death. There was also no statistically significant association between congenital anomalies and the presence of cervical ribs. Our findings support the hypothesis that cervical ribs are markers for disadvantageous developmental events occurring during blastogenesis and have been subject to strong negative selection during evolution.


Subject(s)
Aneuploidy , Cervical Rib Syndrome/epidemiology , Cervical Rib/abnormalities , Fetus/abnormalities , Live Birth/genetics , Stillbirth/genetics , Autopsy , Cervical Rib Syndrome/genetics , Child, Preschool , Comorbidity , Congenital Abnormalities/epidemiology , Congenital Abnormalities/genetics , Female , Humans , Infant , Male , Prevalence , Utah/epidemiology
16.
Appl Immunohistochem Mol Morphol ; 18(3): 231-5, 2010 May.
Article in English | MEDLINE | ID: mdl-20042852

ABSTRACT

CONTEXT: Despite the recognition of the follicular variant of papillary carcinoma of the thyroid (FVPTC) for over 50 years, reproducibility of this diagnostic category has remained poor. Architectural features have been of variable utility as some FVPTC seem encapsulated, whereas others are multifocal and may be confused with nodular hyperplasia. Nuclear features are important for diagnosis of FVPTC, but some authors have discounted the utility of nuclear grooves and inclusions. More recently, BRAF and HBME-1 (Human Bone Marrow Endothelial Cell-1) have been suggested as markers for FVPTC. OBJECTIVE: To investigate the frequency of BRAF mutations and HBME-1 immunopositivity, in a series of FVPTCs in which the diagnosis was established by 100% consensus among a panel of 6 surgical pathologists. DESIGN: Twenty-eight specimens with an original diagnosis of FVPTC and 10 cases with other diagnoses were obtained from the surgical pathology files of the University of Utah School of Medicine. All specimens were independently reviewed by 6 surgical pathologists. Tissue blocks were analyzed for BRAF exon 15 mutations and HMBE-1 expression. RESULTS: Complete agreement among pathologists for the diagnosis of FVPTC was obtained in 28.6% (8/28) of cases originally diagnosed as FVPTC. Mutations in BRAF exon 15 were found in 25% (2/8) of cases with a 100% consensus diagnosis of FVPTC and 32% (6/19) of cases unanimously diagnosed as a type of papillary carcinoma (classic or follicular variant). HBME-1 was expressed in 87.5% (7/8) of lesions with a 100% consensus diagnosis of FVPTC and 84.2% (16/19) of lesions with a unanimous diagnosis of a type of papillary carcinoma of the thyroid (classic or follicular variant). CONCLUSIONS: Interobserver agreement for the diagnosis of FVPTC is poor and testing for the BRAF mutation is only marginally helpful because a minority of FVPTCs possess the mutation. HBME-1 expression when coupled with a BRAF mutation, results in 100% specificity but low sensitivity for the presence of papillary carcinoma of the thyroid including the follicular variant.


Subject(s)
Adenocarcinoma, Follicular/diagnosis , Biomarkers, Tumor/metabolism , Carcinoma, Papillary/diagnosis , Focal Nodular Hyperplasia/diagnosis , Proto-Oncogene Proteins B-raf/metabolism , Thyroid Neoplasms/diagnosis , Adenocarcinoma, Follicular/genetics , Adenocarcinoma, Follicular/metabolism , Adenocarcinoma, Follicular/pathology , Biomarkers, Tumor/immunology , Carcinoma, Papillary/genetics , Carcinoma, Papillary/metabolism , Carcinoma, Papillary/pathology , DNA Mutational Analysis , Diagnosis, Differential , Focal Nodular Hyperplasia/genetics , Focal Nodular Hyperplasia/metabolism , Focal Nodular Hyperplasia/pathology , Humans , Immunohistochemistry , Observer Variation , Proto-Oncogene Proteins B-raf/genetics , Reproducibility of Results , Sensitivity and Specificity , Thyroid Neoplasms/genetics , Thyroid Neoplasms/metabolism , Thyroid Neoplasms/pathology
17.
Proc Natl Acad Sci U S A ; 106(38): 16351-6, 2009 Sep 22.
Article in English | MEDLINE | ID: mdl-19805305

ABSTRACT

Xenotropic murine leukemia virus-related virus (XMRV) was recently discovered in human prostate cancers and is the first gammaretrovirus known to infect humans. While gammaretroviruses have well-characterized oncogenic effects in animals, they have not been shown to cause human cancers. We provide experimental evidence that XMRV is indeed a gammaretrovirus with protein composition and particle ultrastructure highly similar to Moloney murine leukemia virus (MoMLV), another gammaretrovirus. We analyzed 334 consecutive prostate resection specimens, using a quantitative PCR assay and immunohistochemistry (IHC) with an anti-XMRV specific antiserum. We found XMRV DNA in 6% and XMRV protein expression in 23% of prostate cancers. XMRV proteins were expressed primarily in malignant epithelial cells, suggesting that retroviral infection may be directly linked to tumorigenesis. XMRV infection was associated with prostate cancer, especially higher-grade cancers. We found XMRV infection to be independent of a common polymorphism in the RNASEL gene, unlike results previously reported. This finding increases the population at risk for XMRV infection from only those homozygous for the RNASEL variant to all individuals. Our observations provide evidence for an association of XMRV with malignant cells and with more aggressive tumors.


Subject(s)
Gammaretrovirus/physiology , Prostate/virology , Prostatic Neoplasms/virology , Retroviridae Infections/virology , Tumor Virus Infections/virology , Adult , Aged , Base Sequence , Blotting, Western , DNA, Viral/genetics , Endoribonucleases/genetics , Epithelium/pathology , Epithelium/virology , Gammaretrovirus/genetics , Gammaretrovirus/metabolism , Genotype , Host-Pathogen Interactions , Humans , Immunohistochemistry , Male , Microscopy, Electron, Transmission , Middle Aged , Molecular Sequence Data , Polymerase Chain Reaction , Prostate/pathology , Prostatic Neoplasms/pathology , Retroviridae Infections/pathology , Sequence Homology, Nucleic Acid , Tumor Virus Infections/pathology , Viral Load , Viral Proteins/metabolism , Virion/genetics , Virion/immunology , Virion/ultrastructure
18.
JOP ; 10(5): 554-6, 2009 Sep 04.
Article in English | MEDLINE | ID: mdl-19734637

ABSTRACT

CONTEXT: Patients with known or suspected pancreatic adenocarcinoma are typically evaluated with noninvasive imaging studies and endoscopic ultrasound. Rarely, patients require intraoperative evaluation with intraoperative ultrasound to identify mass lesions. Some patients have pancreatic adenocarcinomas that cannot be detected using any of these methods. CASE REPORT: A-58-year old female presented with a distal common bile duct stricture seen on ERCP with negative brushings. Multiple endoscopic ultrasound and triple phase pancreatic protocol CT exams were negative for a mass lesion and revealed a normal pancreas. Intraoperative ultrasound of the pancreas was also felt to be normal. Intraoperative biopsy of the head of the pancreas revealed a small, moderately to poorly differentiated adenocarcinoma, not visible on any of her imaging studies. CONCLUSION: Some pancreatic adenocarcinomas may defy detection using modern imaging modalities. This case illustrates how extensive imaging failed to detect a malignancy prior to surgery. Patients with a high clinical suspicion for malignancy but no visualized mass should undergo operative evaluation with definitive tissue sampling.


Subject(s)
Adenocarcinoma/diagnosis , Diagnostic Errors , Pancreatic Neoplasms/diagnosis , Adenocarcinoma/surgery , Cholangiopancreatography, Endoscopic Retrograde/methods , Delayed Diagnosis , Endosonography/methods , Female , Humans , Intraoperative Period , Middle Aged , Pancreatic Neoplasms/surgery , Tomography, X-Ray Computed/methods , Ultrasonography, Interventional
19.
Environ Health ; 8: 20, 2009 Apr 23.
Article in English | MEDLINE | ID: mdl-19389254

ABSTRACT

BACKGROUND: CYP19 and PPARgamma are two genes expressed in the placental trophoblast that are important to placental function and are disrupted by phthalate exposure in other cell types. Measurement of the mRNA of these two genes in human placental tissue by quantitative real-time polymerase chain reaction (qPCR) offers a source of potential biomarkers for use in epidemiologic research. We report on methodologic challenges to be considered in study design. METHODS: We anonymously collected 10 full-term placentas and, for each, sampled placental villi at 12 sites in the chorionic plate representing the inner (closer to the cord insertion site) and outer regions. Each sample was analyzed for the expression of two candidate genes, aromatase (CYP19) and peroxisome proliferator activated receptor protein gamma (PPARgamma) and three potential internal controls: cyclophilin (CYC), 18S rRNA (18S), and total RNA. Between and within placenta variability was estimated using variance component analysis. Associations of expression levels with sampling characteristics were estimated using mixed effects models. RESULTS: We identified large within-placenta variability in both transcripts (>90% of total variance) that was minimized to <20% of total variance by using 18S as an internal control and by modelling the means by inner and outer regions. 18S rRNA was the most appropriate internal control based on within and between placenta variability estimates and low correlations of 18S mRNA with target gene mRNA. Gene expression did not differ significantly by delivery method. We observed decreases in the expression of both transcripts over the 25 minute period after delivery (CYP19 p-value for trend = 0.009 and PPARgamma (p-value for trend = 0.002). Using histologic methods, we confirmed that our samples were comprised predominantly of villous tissue of the fetal placenta with minimal contamination of maternally derived cell types. CONCLUSION: qPCR-derived biomarkers of placental CYP19 and PPARgamma gene expression show high within-placental variability. Sampling scheme, selection of an appropriate internal control and the timing of sample collection relative to delivery can be optimized to minimize within-placenta and other sources of underlying, non-etiologic variability.


Subject(s)
Aromatase/drug effects , PPAR gamma/drug effects , Phthalic Acids/pharmacology , Placenta/drug effects , Transcription, Genetic/drug effects , Aromatase/metabolism , Biomarkers , Cyclophilins , Female , Gene Expression , Gene Expression Regulation , Humans , PPAR gamma/metabolism , Placenta/metabolism , RNA, Messenger/drug effects , RNA, Messenger/metabolism , RNA, Ribosomal, 18S/drug effects , RNA, Ribosomal, 18S/metabolism , Reverse Transcriptase Polymerase Chain Reaction
20.
J Immunol ; 178(11): 7432-41, 2007 Jun 01.
Article in English | MEDLINE | ID: mdl-17513794

ABSTRACT

Attempts to enhance patients' immune responses to malignancies have been largely unsuccessful. We now describe an immune-escape mechanism mediated by the inhibitory receptor Ig-like transcript 3 (ILT3) that may be responsible for such failures. Using a humanized SCID mouse model, we demonstrate that soluble and membrane ILT3 induce CD8(+) T suppressor cells and prevent rejection of allogeneic tumor transplants. Furthermore, we found that patients with melanoma, and carcinomas of the colon, rectum, and pancreas produce the soluble ILT3 protein, which induces the differentiation of CD8(+) T suppressor cells and impairs T cell responses in MLC. These responses are restored by anti-ILT3 mAb or by depletion of soluble ILT3 from the serum. Immunohistochemical staining of biopsies from the tumors and metastatic lymph nodes suggests that CD68(+) tumor-associated macrophages represent the major source of soluble ILT3. Alternative splicing, resulting in the loss of the ILT3 transmembrane domain, may contribute to the release of ILT3 in the circulation. These data suggest that ILT3 depletion or blockade is crucial to the success of immunotherapy in cancer. In contrast, the inhibitory activity of soluble ILT3 on T cell alloreactivity in vitro and in vivo suggests the potential usefulness of rILT3 for immunosuppressive treatment of allograft recipients or patients with autoimmune diseases.


Subject(s)
Adenocarcinoma/immunology , Colorectal Neoplasms/immunology , Graft Rejection/immunology , Graft Rejection/prevention & control , Melanoma/immunology , Pancreatic Neoplasms/immunology , Receptors, Cell Surface/physiology , T-Lymphocytes, Regulatory/immunology , Adenocarcinoma/metabolism , Adenocarcinoma/pathology , Adult , Aged , Alternative Splicing , Animals , Cell Differentiation/immunology , Cell Line, Tumor , Clonal Anergy , Colorectal Neoplasms/pathology , Disease Progression , Female , Graft Rejection/pathology , Humans , Melanoma/metabolism , Melanoma/pathology , Membrane Glycoproteins , Membrane Proteins/biosynthesis , Membrane Proteins/genetics , Membrane Proteins/physiology , Mice , Mice, Inbred BALB C , Mice, SCID , Middle Aged , Pancreatic Neoplasms/metabolism , Pancreatic Neoplasms/pathology , Receptors, Cell Surface/biosynthesis , Receptors, Cell Surface/blood , Receptors, Cell Surface/genetics , Receptors, Immunologic , T-Lymphocytes, Regulatory/cytology , T-Lymphocytes, Regulatory/pathology , Tumor Escape
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