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1.
Sci Transl Med ; 16(742): eadh8846, 2024 Apr 10.
Artigo em Inglês | MEDLINE | ID: mdl-38598616

RESUMO

Posttransplant lymphoproliferative disease (PTLD) is a major therapeutic challenge that has been difficult to study using human cells because of a lack of suitable models for mechanistic characterization. Here, we show that ex vivo-differentiated B cells isolated from a subset of healthy donors can elicit pathologies similar to PTLD when transferred into immunodeficient mice. The primary driver of PTLD-like pathologies were IgM-producing plasmablasts with Epstein-Barr virus (EBV) genomes that expressed genes commonly associated with EBV latency. We show that a small subset of EBV+ peripheral blood-derived B cells expressing self-reactive, nonmutated B cell receptors (BCRs) expand rapidly in culture in the absence of BCR stimulation. Furthermore, we found that in vitro and in vivo expansion of EBV+ plasmablasts required BCR signaling. Last, treatment of immunodeficient mice with the BCR pathway inhibitor, ibrutinib, delays onset of PTLD-like pathologies in vivo. These data have implications for the diagnosis and care of transplant recipients who are at risk of developing PTLD.


Assuntos
Infecções por Vírus Epstein-Barr , Transtornos Linfoproliferativos , Humanos , Animais , Camundongos , Infecções por Vírus Epstein-Barr/complicações , Infecções por Vírus Epstein-Barr/terapia , Herpesvirus Humano 4 , Transtornos Linfoproliferativos/terapia , Transdução de Sinais , Linfócitos B
2.
Nat Commun ; 13(1): 6110, 2022 10 16.
Artigo em Inglês | MEDLINE | ID: mdl-36245034

RESUMO

Due to their unique longevity and capacity to secrete high levels of protein, plasma B cells have the potential to be used as a cell therapy for protein replacement. Here, we show that ex vivo engineered human plasma cells exhibit single-cell RNA profiles, scanning electron micrograph ultrastructural features, and in vivo homing capacity of long-lived plasma cells. After transferring human plasma cells to immunodeficient mice in the presence of the human cytokines BAFF and IL-6, we observe increases in retention of plasma cells in the bone marrow, with engraftment exceeding a year. The most profound in vivo effects of human IL-6 are observed within 20 days of transfer and could be explained by decreased apoptosis in newly differentiated plasma cells. Collectively, these results show that ex vivo engineered and differentiated human plasma cells have the potential for long-lived in vivo protein secretion, which can be modeled in small animals.


Assuntos
Transplante de Células-Tronco Hematopoéticas , Plasmócitos , Animais , Proteínas Sanguíneas , Citocinas/metabolismo , Humanos , Interleucina-6 , Camundongos , Camundongos SCID , Plasmócitos/metabolismo , RNA
3.
Cell Rep Med ; 1(3)2020 06 23.
Artigo em Inglês | MEDLINE | ID: mdl-32724901

RESUMO

Epstein-Barr virus (EBV) is a cancer-associated pathogen for which there is no vaccine. Successful anti-viral vaccines elicit antibodies that neutralize infectivity; however, it is unknown whether neutralizing antibodies prevent EBV acquisition. Here we assessed whether passively delivered AMMO1, a monoclonal antibody that neutralizes EBV in a cell-type-independent manner, could protect against experimental EBV challenge in two animal infection models. When present prior to a high-dose intravenous EBV challenge, AMMO1 prevented viremia and reduced viral loads to nearly undetectable levels in humanized mice. AMMO1 conferred sterilizing immunity to three of four macaques challenged orally with rhesus lymphocryptovirus, the EBV ortholog that infects rhesus macaques. The infected macaque had lower plasma neutralizing activity than the protected animals. These results indicate that a vaccine capable of eliciting adequate titers of neutralizing antibodies targeting the AMMO1 epitope may protect against EBV acquisition and are therefore highly relevant to the design of an effective EBV vaccine.


Assuntos
Anticorpos Neutralizantes/imunologia , Infecções por Herpesviridae/imunologia , Lymphocryptovirus/imunologia , Animais , Anticorpos Monoclonais/imunologia , Anticorpos Antivirais/imunologia , Células CHO , Linhagem Celular , Cricetulus , Epitopos/imunologia , Feminino , Células HEK293 , Infecções por Herpesviridae/virologia , Humanos , Macaca mulatta/imunologia , Macaca mulatta/virologia , Masculino , Camundongos , Carga Viral/métodos , Viremia/imunologia , Viremia/virologia
4.
Nat Biomed Eng ; 3(4): 281-291, 2019 04.
Artigo em Inglês | MEDLINE | ID: mdl-30952979

RESUMO

The early detection of the onset of transplant rejection is critical for the long-term survival of patients. The diagnostic gold standard for detecting transplant rejection involves a core biopsy, which is invasive, has limited predictive power and carries a morbidity risk. Here, we show that nanoparticles conjugated with a peptide substrate specific for the serine protease granzyme B, which is produced by recipient T cells during the onset of acute cellular rejection, can serve as a non-invasive biomarker of early rejection. When administered systemically in mouse models of skin graft rejection, these nanosensors preferentially accumulate in allograft tissue, where they are cleaved by granzyme B, releasing a fluorescent reporter that filters into the recipient's urine. Urinalysis then discriminates the onset of rejection with high sensitivity and specificity before features of rejection are apparent in grafted tissues. Moreover, in mice treated with subtherapeutic levels of immunosuppressive drugs, the reporter signals in urine can be detected before graft failure. This method may enable routine monitoring of allograft status without the need for biopsies.


Assuntos
Técnicas Biossensoriais , Rejeição de Enxerto/diagnóstico , Granzimas/metabolismo , Transplante de Rim/efeitos adversos , Nanopartículas/química , Animais , Morte Celular , Granzimas/farmacocinética , Granzimas/urina , Terapia de Imunossupressão , Masculino , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Linfócitos T/imunologia , Regulação para Cima
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