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1.
Transplant Cell Ther ; 2024 Jul 04.
Article in English | MEDLINE | ID: mdl-38972510

ABSTRACT

BACKGROUND: Conditioning regimens for hematopoietic cell transplant (HCT) in patients with sickle cell disease (SCD) place patients at risk for reproductive health issues. OBJECTIVE: The purpose of this study was to assess reproductive health and reports of fertility counseling in patients with SCD who received a transplant. STUDY DESIGN: This was a secondary analysis of gonadal hormone production, future infertility risk assessment and parent-proxy/patient reports of fertility counseling in SCD transplant recipients who are currently pubertal and were enrolled in the Atlanta sites of the Sickle Cell Transplant Evaluation of Long-term and Late Effects Registry (STELLAR) between May 2017 and October 2023. Clinical information was abstracted from medical records and reproductive health survey data from the STELLAR database. Descriptive statistics were reported as median (IQR) or percentages. RESULTS: There were 20 females and 12 males in the study population. Females were median (IQR) 19.6 (9.4) years old and males 20.8 (11.4) years old at the time of the study. Transplants most commonly occurred in the decade 2010 - 2019 at 10.7 (4.8) years old for females and 11.1 (4.1) years old for males. Most participants received bone marrow stem cells (95.0% females, 100.0% males) from matched sibling donors (90.0% females, 100.0% males). Participants received one of seven HCT conditioning regimens with cyclophosphamide equivalent doses ranging from 3,388mg/m2 to 9,706mg/m2. The majority of females (90.0%) had diminished ovarian reserve with low anti-Mullerian hormone levels, and 61.1% had premature ovarian insufficiency with two follicle-stimulating hormone levels (FSH) ≥ 40 mIU/mL post-HCT. All males had normal testosterone levels, but 63.6% had elevated FSH levels suggestive of impaired spermatogenesis post-HCT. Parent-proxies (for patients < 18 years old) and patients ≥ 18 years old completed surveys 9.0 years (5.2) and 7.9 years (9.3) since HCT in females and males respectively. Twenty five percent of parent-proxies and 45% of patients reported that they had not been informed by a healthcare provider of the risk of infertility post-transplant. CONCLUSION: There are high rates of gonadal dysfunction post-HCT, but many parent-proxies and patients do not recall being told of the risk for future infertility. More effective methods of education are warranted to ensure SCD patients and their families clearly understand the risk for reproductive health issues post-HCT.

2.
Fertil Steril ; 114(3): 567-578, 2020 09.
Article in English | MEDLINE | ID: mdl-32680613

ABSTRACT

OBJECTIVES: To assess trends, predictors, and perinatal outcomes of ovarian hyperstimulation syndrome (OHSS) associated with in vitro fertilization (IVF) cycles in the United States. DESIGN: Retrospective cohort study using National Assisted Reproductive Technology Surveillance System (NASS) data. SETTING: Not applicable. PATIENT(S): Fresh autologous and embryo-banking cycles performed from 2000 to 2015. INTERVENTIONS(S): None. MAIN OUTCOME MEASURE(S): OHSS, first-trimester loss, second-trimester loss, stillbirth, low birth weight, and preterm delivery. RESULT(S): The proportion of IVF cycles complicated by OHSS increased from 10.0 to 14.3 cases per 1,000 from 2000 to 2006, and decreased to 5.3 per 1,000 from 2006 to 2015. The risk of OHSS was highest for cycles with more than 30 oocytes retrieved (adjusted risk ratio [aRR] 3.85). OHSS was associated with a diagnosis of ovulatory disorder (aRR 2.61), tubal factor (aRR 1.14), uterine factor (aRR 1.17) and cycles resulting in pregnancy (aRR 3.12). In singleton pregnancies, OHSS was associated with increased risk of low birth weight (aRR 1.29) and preterm delivery (aRR 1.32). In twin pregnancies, OHSS was associated with an increased risk of second-trimester loss (aRR 1.81), low birth weight (aRR 1.06), and preterm delivery (aRR 1.16). CONCLUSION(S): Modifiable predictive factors for OHSS include number of oocytes retrieved, pregnancy following fresh embryo transfer, and the type of medication used for pituitary suppression during controlled ovarian hyperstimulation. Patients affected by OHSS had a higher risk of preterm delivery and low birth weight. Clinicians should take measures to reduce the risk of OHSS whenever possible.


Subject(s)
Fertility Agents, Female/adverse effects , Infertility/therapy , Ovarian Hyperstimulation Syndrome/chemically induced , Ovulation Induction/adverse effects , Ovulation/drug effects , Abortion, Spontaneous/epidemiology , Adult , Birth Weight , Databases, Factual , Female , Fertilization in Vitro/adverse effects , Gestational Age , Humans , Infant, Low Birth Weight , Infant, Newborn , Infant, Premature , Infertility/diagnosis , Infertility/epidemiology , Infertility/physiopathology , Oocyte Retrieval/adverse effects , Ovarian Hyperstimulation Syndrome/diagnosis , Ovarian Hyperstimulation Syndrome/epidemiology , Ovarian Hyperstimulation Syndrome/physiopathology , Ovulation Induction/trends , Pregnancy , Pregnancy Outcome , Premature Birth/epidemiology , Retrospective Studies , Risk Assessment , Risk Factors , Stillbirth/epidemiology , Time Factors , Treatment Outcome , United States/epidemiology
3.
Cells ; 9(7)2020 06 29.
Article in English | MEDLINE | ID: mdl-32610710

ABSTRACT

In this study we report the functional comparison of T cell receptor (TCR)-engineered major histocompatibility complex (MHC) class I-restricted CD4+ versus CD8+ T cells targeting a peptide from six transmembrane epithelial antigen of the prostate 1 (STEAP1) in the context of HLA-A*02:01. STEAP1 is a tumor-associated antigen, which is overexpressed in many cancers, including Ewing sarcoma (EwS). Based on previous observations, we postulated strong antitumor potential of tumor-redirected CD4+ T cells transduced with an HLA class I-restricted TCR against a STEAP1-derived peptide. We compared CD4+ T cell populations to their CD8+ counterparts in vitro using impedance-based xCELLigence and cytokine/granzyme release assays. We further compared antitumor activity of STEAP130-TCR transgenic (tg) CD4+ versus CD8+ T cells in tumor-bearing xenografted Rag2-/-gc-/- mice. TCR tgCD4+ T cells showed increased cytotoxic features over time with similar functional avidity compared to tgCD8+ cells after 5-6 weeks of culture. In vivo, local tumor control was equal. Assessing metastatic organotropism of intraveniously (i.v.) injected tumors, only tgCD8+ cells were associated with reduced metastases. In this analysis, EwS-redirected tgCD4+ T cells contribute to local tumor control, but fail to control metastatic outgrowth in a model of xenografted EwS.


Subject(s)
Antigens, Neoplasm/metabolism , CD4-Positive T-Lymphocytes/metabolism , CD8-Positive T-Lymphocytes/metabolism , Oxidoreductases/metabolism , Sarcoma, Ewing/metabolism , Animals , Cells, Cultured , Computational Biology , DNA-Binding Proteins/metabolism , Flow Cytometry , Humans , Mice, Inbred BALB C , Mice, Mutant Strains , Xenograft Model Antitumor Assays
4.
J Adolesc Young Adult Oncol ; 8(1): 18-25, 2019 02.
Article in English | MEDLINE | ID: mdl-30281375

ABSTRACT

PURPOSE: Current guidelines recommend screening at-risk childhood cancer survivors for ovarian dysfunction using follicle-stimulating hormone (FSH). However, FSH identifies diminished ovarian reserve (DOR), a component of ovarian dysfunction, in the later stages when fertility preservation is less likely to succeed. This analysis evaluates the utility of anti-Mullerian hormone (AMH) for the assessment of DOR in adolescent and young adult (AYA)-aged survivors of childhood cancer. METHODS: A retrospective chart review of 13- to 21-year-old female survivors who received gonadotoxic therapy and were ≥2 years off therapy was performed. Gonadotoxic treatments were categorized as low, moderate, or high risk for future infertility. Patients with AMH below the assay's age-specific normal range were identified and stratified by FSH values (normal ≤12 mIU/mL). Prevalence of low AMH and AMH-FSH subgroups was calculated and risk factors were evaluated using logistic regression. RESULTS: AMH was measured in 190 survivors who received gonadotoxic treatment; of them, 35.3% had low AMH. Among survivors who received <30 Gy cranial radiation and were not on hormone therapy (n = 141), 18.4% had normal FSH with low AMH. Stratified by future infertility risk, 10.6% of low-risk, 38.1% of moderate-risk, and 25.7% of high-risk survivors had normal FSH with low AMH (p < 0.01). Within the low-risk group, normal FSH with low AMH was significantly associated with older age at diagnosis (p = 0.02). CONCLUSION: Nearly 20% of AYA-aged at-risk survivors had low AMH and normal FSH. DOR in these patients would have been missed in standard recommended surveillance practices.


Subject(s)
Anti-Mullerian Hormone/metabolism , Cancer Survivors/statistics & numerical data , Ovarian Diseases/diagnosis , Ovarian Reserve/physiology , Adolescent , Adult , Early Diagnosis , Female , Humans , Ovarian Diseases/mortality , Retrospective Studies , Survivorship , Young Adult
5.
Rev Endocr Metab Disord ; 19(3): 231-242, 2018 09.
Article in English | MEDLINE | ID: mdl-30219984

ABSTRACT

Gender affirming procedures adversely affect the reproductive potential of transgender people. Thus, fertility preservation options should be discussed with all transpeople before medical and surgical transition. In transwomen, semen cryopreservation is typically straightforward and widely available at fertility centers. The optimal number of vials frozen depends on their reproductive goals and treatment options, therefore a consultation with a fertility specialist is optimal. Experimental techniques including spermatogonium stem cells (SSC) and testicular tissue preservation are technologies currently under development in prepubertal individuals but are not yet clinically available. In transmen, embryo and/or oocyte cryopreservation is currently the best option for fertility preservation. Embryo cryopreservation requires fertilization of the transman's oocytes with a donor or partner's sperm prior to cryopreservation, but this limits his future options for fertilizing the eggs with another partner or donor. Oocyte cryopreservation offers transmen the opportunity to preserve their fertility without committing to a male partner or sperm donor at the time of cryopreservation. Both techniques however require at least a two-week treatment course, egg retrieval under sedation and considerable cost. Ovarian tissue cryopreservation is a promising experimental method that may be performed at the same time as gender affirming surgery but is offered in only a limited amount of centers worldwide. In select places, this method may be considered for prepubertal children, adolescents, and adults when ovarian stimulation is not possible. Novel methods such as in-vitro activation of primordial follicles, in vitro maturation of immature oocytes and artificial gametes are under development and may hold promise for the future.


Subject(s)
Fertility Preservation/methods , Transgender Persons , Cryopreservation/methods , Female , Humans , Male , Reproduction/physiology
7.
Article in English | MEDLINE | ID: mdl-29507740

ABSTRACT

BACKGROUND: Fungal cyclodepsipeptides (CDPs) are non-ribosomally synthesized peptides produced by a variety of filamentous fungi and are of interest to the pharmaceutical industry due to their anticancer, antimicrobial and anthelmintic bioactivities. However, both chemical synthesis and isolation of CDPs from their natural producers are limited due to high costs and comparatively low yields. These challenges might be overcome by heterologous expression of the respective CDP-synthesizing genes in a suitable fungal host. The well-established industrial fungus Aspergillus niger was recently genetically reprogrammed to overproduce the cyclodepsipeptide enniatin B in g/L scale, suggesting that it can generally serve as a high production strain for natural products such as CDPs. In this study, we thus aimed to determine whether other CDPs such as beauvericin and bassianolide can be produced with high titres in A. niger, and whether the generated expression strains can be used to synthesize new-to-nature CDP derivatives. RESULTS: The beauvericin and bassianolide synthetases were expressed under control of the tuneable Tet-on promoter, and titres of about 350-600 mg/L for bassianolide and beauvericin were achieved when using optimized feeding conditions, respectively. These are the highest concentrations ever reported for both compounds, whether isolated from natural or heterologous expression systems. We also show that the newly established Tet-on based expression strains can be used to produce new-to-nature beauvericin derivatives by precursor directed biosynthesis, including the compounds 12-hydroxyvalerate-beauvericin and bromo-beauvericin. By feeding deuterated variants of one of the necessary precursors (d-hydroxyisovalerate), we were able to purify deuterated analogues of beauvericin and bassianolide from the respective A. niger expression strains. These deuterated compounds could potentially be used as internal standards in stable isotope dilution analyses to evaluate and quantify fungal spoilage of food and feed products. CONCLUSION: In this study, we show that the product portfolio of A. niger can be expanded from enniatin to other CDPs such as beauvericin and bassianolide, as well as derivatives thereof. This illustrates the capability of A. niger to produce a range of different peptide natural products in titres high enough to become industrially relevant.

8.
Oncoimmunology ; 6(5): e1312239, 2017.
Article in English | MEDLINE | ID: mdl-28638739

ABSTRACT

Background: Chondromodulin-I (CHM1) sustains malignancy in Ewing sarcoma (ES). Refractory ES carries a dismal prognosis and patients with bone marrow (BM) metastases do not survive irrespective of therapy. We assessed HLA-A*02:01/CHM1-specific allorestricted T cell receptor (TCR) wild-type and transgenic cytotoxic (CD8+) T cells against ES. Patients and Methods: Three refractory HLA-A2+ ES patients were treated with HLA-A*02:01/peptide-specific allorepertoire-derived (i.e., allorestricted) CD8+ T cells. Patient #1 received up to 4.8 × 105/kg body weight HLA-A*02:01- allorestricted donor-derived wild-type CD8+ T cells. Patient #2 received up to 8.2 × 106/kg HLA-A*02:01- donor-derived and patient #3 up to 6 × 106/kg autologous allorestricted TCR transgenic CD8+ T cells. All patients were treated with the same TCR complementary determining region 3 allorecognition sequence for CHM1 peptide 319 (CHM1319). Results: HLA-A*02:01/CHM1319-specific allorestricted CD8+ T cells showed specific in vitro lysis of all patient-derived ES cell lines. Therapy was well tolerated and did not cause graft versus host disease (GvHD). Patients #1 and #3 showed slow progression, whereas patient #2, while having BM involvement, showed partial metastatic regression associated with T cell homing to involved lesions. CHM1319 TCR transgenic T cells could be tracked in his BM for weeks. Conclusions: CHM1319-TCR transgenic T cells home to affected BM and may cause partial disease regression. HLA-A*02:01/antigen-specific allorestricted T cells proliferate in vivo without causing GvHD.

9.
Mol Oncol ; 11(9): 1288-1301, 2017 09.
Article in English | MEDLINE | ID: mdl-28319320

ABSTRACT

Ewing sarcomas (ES) are highly malignant, osteolytic bone or soft tissue tumors, which are characterized by EWS-ETS translocations and early metastasis to lung and bone. In this study, we investigated the role of the BRICHOS chaperone domain-containing endochondral bone protein chondromodulin I (CHM1) in ES pathogenesis. CHM1 is significantly overexpressed in ES, and chromosome immunoprecipitation (ChIP) data demonstrate CHM1 to be directly bound by an EWS-ETS translocation, EWS-FLI1. Using RNA interference, we observed that CHM1 promoted chondrogenic differentiation capacity of ES cells but decreased the expression of osteolytic genes such as HIF1A, IL6, JAG1, and VEGF. This was in line with the induction of the number of tartrate-resistant acid phosphatase (TRAP+ )-stained osteoclasts in an orthotopic model of local tumor growth after CHM1 knockdown, indicating that CHM1-mediated inhibition of osteomimicry might play a role in homing, colonization, and invasion into bone tissues. We further demonstrate that CHM1 enhanced the invasive potential of ES cells in vitro. This invasiveness was in part mediated via CHM1-regulated matrix metallopeptidase 9 expression and correlated with the observation that, in an xenograft mouse model, CHM1 was essential for the establishment of lung metastases. This finding is in line with the observed increase in CHM1 expression in patient specimens with ES lung metastases. Our results suggest that CHM1 seems to have pleiotropic functions in ES, which need to be further investigated, but appears to be essential for the invasive and metastatic capacities of ES.


Subject(s)
Cell Differentiation , Intercellular Signaling Peptides and Proteins/metabolism , Lung Neoplasms/secondary , Membrane Proteins/metabolism , Sarcoma, Ewing/pathology , Animals , Cell Differentiation/genetics , Cell Line, Tumor , Cell Proliferation , Chondrocytes/metabolism , Chondrocytes/pathology , Endothelial Cells/metabolism , Endothelial Cells/pathology , Gene Expression Regulation, Neoplastic , Humans , Intercellular Signaling Peptides and Proteins/genetics , Lung Neoplasms/pathology , Membrane Proteins/genetics , Mice, Inbred BALB C , Neoplasm Invasiveness , Phenotype , Sarcoma, Ewing/genetics
10.
Semin Reprod Med ; 34(5): 261-265, 2016 09.
Article in English | MEDLINE | ID: mdl-27618294

ABSTRACT

Over the past year, the Zika virus, an arthropod-borne Flavivirus, has transitioned from a relatively unknown tropical disease to the cause of a public health emergency. The Zika virus is transmitted by the Aedes species of mosquito as well as by sexual intercourse. Although the symptoms of acute Zika virus infection are usually mild and self-limited, it causes fetal microcephaly in pregnant women, and is associated with an increased risk of Guillain-Barré syndrome. The risk of microcephaly from Zika virus infection is estimated to be highest in women who are infected during the first trimester of pregnancy. The Zika virus has been shown to have significant neurotrophism in vivo and in vitro, although further study is needed to characterize its mechanisms of pathogenesis. Zika virus has previously caused two known outbreaks in the Pacific region prior to the current epidemic in South and Central America, and the current epidemic has affected at least 440,000 to 1,300,000 people. The population of the vector for the current epidemic, Aedes aegypti, varies seasonally in the United States, however there have been few documented cases of local spread of the Zika infection in the United States and it is unclear whether epidemic spread of Zika will occur within the United States.


Subject(s)
Aedes/virology , Disease Outbreaks , Disease Vectors , Guillain-Barre Syndrome/virology , Microcephaly/virology , Pregnancy Complications, Infectious/virology , Sexually Transmitted Diseases, Viral/virology , Zika Virus Infection/virology , Zika Virus/pathogenicity , Animals , Female , Guillain-Barre Syndrome/epidemiology , Humans , Male , Microcephaly/epidemiology , Pregnancy , Pregnancy Complications, Infectious/epidemiology , Pregnancy Trimester, First , Prognosis , Risk Factors , Sexually Transmitted Diseases, Viral/epidemiology , Sexually Transmitted Diseases, Viral/transmission , Zika Virus Infection/epidemiology , Zika Virus Infection/transmission
11.
Oncoimmunology ; 5(6): e1175795, 2016 Jun.
Article in English | MEDLINE | ID: mdl-27471654

ABSTRACT

Pediatric cancers, including Ewing sarcoma (ES), are only weakly immunogenic and the tumor-patients' immune system often is devoid of effector T cells for tumor elimination. Based on expression profiling technology, targetable tumor-associated antigens (TAA) are identified and exploited for engineered T-cell therapy. Here, the specific recognition and lytic potential of transgenic allo-restricted CD8(+) T cells, directed against the ES-associated antigen 6-transmembrane epithelial antigen of the prostate 1 (STEAP1), was examined. Following repetitive STEAP1(130) peptide-driven stimulations with HLA-A*02:01(+) dendritic cells (DC), allo-restricted HLA-A*02:01(-) CD8(+) T cells were sorted with HLA-A*02:01/peptide multimers and expanded by limiting dilution. After functional analysis of suitable T cell clones via ELISpot, flow cytometry and xCELLigence assay, T cell receptors' (TCR) α- and ß-chains were identified, cloned into retroviral vectors, codon optimized, transfected into HLA-A*02:01(-) primary T cell populations and tested again for specificity and lytic capacity in vitro and in a Rag2(-/-)γc(-/-) mouse model. Initially generated transgenic T cells specifically recognized STEAP1(130)-pulsed or transfected cells in the context of HLA-A*02:01 with minimal cross-reactivity as determined by specific interferon-γ (IFNγ) release, lysed cells and inhibited growth of HLA-A*02:01(+) ES lines more effectively than HLA-A*02:01(-) ES lines. In vivo tumor growth was inhibited more effectively with transgenic STEAP1(130)-specific T cells than with unspecific T cells. Our results identify TCRs capable of recognizing and inhibiting growth of STEAP1-expressing HLA-A*02:01(+) ES cells in vitro and in vivo in a highly restricted manner. As STEAP1 is overexpressed in a wide variety of cancers, we anticipate these STEAP1-specific TCRs to be potentially useful for immunotherapy of other STEAP1-expressing tumors.

12.
Oncotarget ; 7(28): 43267-43280, 2016 Jul 12.
Article in English | MEDLINE | ID: mdl-27281613

ABSTRACT

The endochondral bone protein Chondromodulin-I (CHM1) provides oncogene addiction in Ewing sarcoma (ES). We pre-clinically tested the targetability of CHM1 by TCR transgenic, allo-restricted, peptide specific T cells to treat ES. We previously generated allo-restricted wildtype CD8+ T cells directed against the ES specific antigen CHM1319 causing specific responses against ES. However, utilization of these cells in current therapy protocols is hampered due to high complexity in production, relatively low cell numbers, and rapid T cell exhaustion.In order to provide off-the-shelf products in the future, we successfully generated HLA-A*02:01-restricted T cell receptor (TCR) transgenic T cells directed against CHM1319 by retroviral transduction.After short-term expansion a 100% purified CHM1319-TCR-transgenic T cell population expressed a CD62L+/CD45RO and CD62L+/CD45RA+ phenotype. These cells displayed specific in vitro IFNg and granzyme B release in co-culture with HLA-A*02:01+ ES cell lines expressing CHM1. When co-injected with ES cells in Rag2-/-É£c-/- mice, CHM1-specific TCR-transgenic T cells significantly inhibited the formation of lung and liver metastases in contrast to control mice. Lungs and livers of representative mice displayed CD8+ T cell infiltration in the presence (control group treated with unspecific T cells) and in the absence (study group) of metastatic disease, respectively. Furthermore, mice receiving unspecific T cells showed signs of graft-versus-host-disease in contrast to all mice, receiving CHM1319-TCR-transgenic T cells.CHM1319 specific TCR-transgenic T cells were successfully generated causing anti-ES responses in vitro and in vivo. In the future, CHM1319-TCR-transgenic T cells may control minimal residual disease rendering donor lymphocyte infusions more efficacious and less toxic.


Subject(s)
CD8-Positive T-Lymphocytes/transplantation , Hematopoietic Stem Cell Transplantation/methods , Immunotherapy, Adoptive/methods , Intercellular Signaling Peptides and Proteins/metabolism , Membrane Proteins/metabolism , Sarcoma, Ewing/therapy , Animals , CD8-Positive T-Lymphocytes/immunology , CD8-Positive T-Lymphocytes/metabolism , Cell Line, Tumor , Coculture Techniques , DNA-Binding Proteins/genetics , Graft vs Host Disease/immunology , Granzymes/metabolism , HLA-A Antigens/genetics , HLA-A Antigens/immunology , Hematopoietic Stem Cell Transplantation/adverse effects , Humans , Immunotherapy, Adoptive/adverse effects , Interferon-gamma/metabolism , Liver/pathology , Lung/pathology , Mice , Mice, Inbred BALB C , Oncogene Addiction , Receptors, Antigen, T-Cell/genetics , Retroviridae/genetics , Sarcoma, Ewing/immunology , Sarcoma, Ewing/pathology , Transduction, Genetic , Transplantation, Homologous/adverse effects , Transplantation, Homologous/methods
13.
Blood ; 112(3): 891-4, 2008 Aug 01.
Article in English | MEDLINE | ID: mdl-18483395

ABSTRACT

Cytokines are hypothesized to play a central role in the pathophysiology of IgG-mediated hemolytic transfusion reactions (HTRs), and deeper understanding is required for improving therapy for these events. After establishing well-defined mouse models of HTRs, we tested whether cytokines were involved. Red blood cells (RBCs) from human glycophorin A transgenic (hGPA-Tg) or wild-type (WT) mice were transfused into non-Tg recipients passively immunized with monoclonal antibodies (Mabs). Only transfusions of incompatible RBCs induced IgG-mediated HTRs, exemplified by rapid clearance and hemoglobinuria. Very high plasma levels of monocyte chemoattractant protein-1 (MCP-1) and interleukin-6 (IL-6), and lower levels of tumor necrosis factor-alpha (TNF-alpha), were induced after incompatible transfusion. No significant changes in IL-10, IL-12, or interferon-gamma (IFN-gamma) levels were observed. The proinflammatory cytokines elaborated in this in vivo mouse model are also implicated in the systemic inflammatory response syndrome (SIRS) and confirm the hypothesis that cytokine storm occurs as a result of HTRs.


Subject(s)
Cytokines/biosynthesis , Hemolysis/immunology , Transfusion Reaction , Animals , Blood Group Incompatibility , Glycophorins , Humans , Immunoglobulin G , Inflammation , Mice , Mice, Transgenic , Models, Animal
14.
Blood ; 110(6): 2201-8, 2007 Sep 15.
Article in English | MEDLINE | ID: mdl-17569819

ABSTRACT

Transfusion of crossmatch-incompatible red blood cells (RBCs) can result in antibody-mediated hemolysis. However, in some patients, crossmatch-incompatible RBCs lose the incompatible antigen from their surface, and then circulate normally ("antigen loss"). Although antigen loss has been reported in the settings of autoimmune hemolytic anemia and transfusion of crossmatch-incompatible RBCs, mechanistic understanding of this phenomenon is limited. Using an in vivo murine model of antigen loss, we report that, unlike polyclonal antisera, monoclonal antibodies did not induce antigen loss. However, the combination of 2 monoclonal antibodies that recognized separate epitopes on the same antigen induced antigen loss. This was not due to an increased number of Fc domains bound to the cell surface, because antigen loss still occurred when combining intact monoclonal IgG and F(ab')2 fragments recognizing different epitopes. Together, these data lead to the hypothesis that antigen-antibody crosslinking is required for nonhemolytic antigen loss to occur.


Subject(s)
Antibodies, Monoclonal/immunology , Antigen-Antibody Reactions/immunology , Antigens, Surface/immunology , Epitopes/immunology , Erythrocytes/immunology , Animals , Antibodies, Monoclonal/metabolism , Antigens, Surface/metabolism , Epitopes/metabolism , Erythrocytes/metabolism , Flow Cytometry , Immunoglobulin Fab Fragments/immunology , Immunoglobulin Fc Fragments/immunology , Immunoglobulin G/immunology , Mice , Mice, Inbred BALB C , Mice, Inbred C3H , Mice, Inbred C57BL , Muramidase/immunology , Muramidase/metabolism
15.
Blood ; 109(7): 3099-107, 2007 Apr 01.
Article in English | MEDLINE | ID: mdl-17119123

ABSTRACT

Well-characterized mouse models of allo-immune antibody-mediated hemolysis would provide a valuable approach for gaining greater insight into the pathophysiology of hemolytic transfusion reactions. To this end, mouse red blood cells (mRBCs) from human glycophorin A transgenic (hGPA-Tg) donor mice were transfused into non-Tg recipients that had been passively immunized with IgG or IgM hGPA-specific monoclonal antibodies (mAbs). In this novel murine "blood group system," mRBCs from hGPA-Tg mice are "antigen positive" and mRBCs from non-Tg mice are "antigen negative." Passive immunization of non-Tg mice with the IgG1 10F7 and IgG3 NaM10-2H12 anti-hGPA mAbs each induced rapid clearance of incompatible transfused hGPA-Tg-mRBCs in a dose-response manner. Using various knockout mice as transfusion recipients, both the complement system and activating Fcgamma receptors were found to be important in the clearance of incompatible mRBCs by each of these IgG mAbs. In addition, the IgM E4 anti-hGPA mAb induced complement-dependent intravascular hemolysis of transfused incompatible hGPA-Tg-mRBCs accompanied by gross hemoglobinuria. These initial studies validate the relevance of these new mouse models for addressing important questions in the field of transfusion medicine.


Subject(s)
Hemolysis/immunology , Immunoglobulin G/blood , Immunoglobulin M/blood , Transfusion Reaction , Animals , Antibodies, Monoclonal , Complement System Proteins/metabolism , Disease Models, Animal , Glycophorins/genetics , Humans , Immunization, Passive , In Vitro Techniques , Isoantibodies/blood , Mice , Mice, Inbred BALB C , Mice, Inbred C57BL , Mice, Knockout , Mice, Transgenic , Receptors, IgG/blood
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