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1.
J Immunol ; 2024 Jun 12.
Artículo en Inglés | MEDLINE | ID: mdl-38864663

RESUMEN

Allogeneic hematopoietic cell transplantation is an effective treatment for hematologic malignancies, but the complications such as graft-versus-host disease (GVHD) can limit its benefit. The conditioning regimens before transplant, including chemotherapy or irradiation, can trigger endoplasmic reticulum stress. IRE-1α is a major endoplasmic reticulum stress mediator that can further activate both spliced XBP-1 (XBP-1s) and regulated IRE-1-dependent decay (RIDD). IRE-1α-XBP-1s signaling controls dendritic cell (DC) differentiation and Ag presentation, crucial in GVHD progression. In this study, we used DC-specific XBP-1-deficient mice as donors or recipients and observed that XBP-1s was crucial for host DCs in the induction of GVHD but dispensable for the graft-versus-leukemia response. To specifically target IRE-1α in the host, we treated recipient mice with the IRE-1α inhibitor B-I09 for 3 d prior to bone marrow transplantation, which significantly suppressed GVHD development while maintaining the graft-versus-leukemia effect. XBP-1-deficient or BI09-treated recipients showed reduced DC survival after irradiation and bone marrow transplantation. Inhibition of IRE-1α also led to a reduction in DC alloreactivity, subsequently decreasing the proliferation and activation of allogeneic T cells. With further study using RIDD-deficient DCs, we observed that RIDD was also required for optimal DC activation. Taken together, XBP-1s and RIDD both promote host DC survival and alloreactivity that contribute to GVHD development.

2.
Pathophysiology ; 26(3-4): 233-244, 2019.
Artículo en Inglés | MEDLINE | ID: mdl-31248669

RESUMEN

Allogeneic hematopoietic stem cell transplantation (HSCT) is a potentially life-saving treatment for refractory/relapsing hematological malignancies, blood disorders or autoimmune diseases. However, approximately 40-50% of patients undergoing allogeneic HSCT will develop a multi-organ, inflammatory disorder called acute graft vs. host disease (aGVHD). Experimental and clinical studies suggest that intestinal injury due to toxic, pre-transplant conditioning protocols (e.g. lethal irradiation and/or chemotherapy) may play a major role in the development of aGVHD. However, recent studies from our laboratory suggest that this may not be the case. The objective of this study was to quantify and compare the onset and severity of aGVHD induced by the adoptive transfer of allogeneic T cells into untreated lymphopenic mice. Four million allogeneic or syngeneic CD4+CD62L+CD25- T cells were transferred (i.p.) into NK cell-depleted RAG1-/- mice or RAG2-/-IL2rγ-/-double knock-out (DKO) mice and assessed daily for signs of aGVHD. We found that adoptive transfer of allogeneic but not syngeneic T cells into NK cell-depleted RAG1-/- or DKO mice induced many of the clinical and histological features of aGVHD including weight loss, inflammatory cytokine production and tissue inflammation. In addition, adoptive transfer of allogeneic T cells into each recipient induced severe anemia as well as dramatic reductions in bone marrow and spleen cellularity. Taken together, we conclude that allogeneic CD4+ T cells are both necessary and sufficient to induce aGVHD in lymphopenic recipients in the absence of toxic, pre-transplant conditioning.

3.
J Physiol ; 596(17): 3915-3927, 2018 09.
Artículo en Inglés | MEDLINE | ID: mdl-29574759

RESUMEN

It is well known that alterations in splanchnic organ perfusion and/or immune regulation may produce inflammatory tissue injury similar to that observed in several human disorders such as ischaemia and reperfusion injury, food allergies, diabetes, inflammatory bowel disease and graft-versus-host disease. Mouse models have been tremendously important in defining the roles of the circulation, leukocyte trafficking, inflammatory mediator generation, immune regulation and the intestinal microbiota in the pathogenesis of acute and chronic inflammation. However, few of the promising interventions or therapeutics reported in mouse models of inflammatory diseases have been translated to clinically effective treatments in patients. There is growing concern that because of the significant differences that exist between the murine and human immune systems, mouse models may not adequately recapitulate the immuno-pathogenesis of inflammatory diseases. This inconvenient reality has prompted a number of investigators to undertake a series of studies to humanize the murine immune system via adoptive transfer of human lymphoid or progenitor cells into a new generation of immuno-deficient recipients. In this review, we summarize the recent advances that have been made in the development of humanized mice and describe how these mouse models are being used to study the pathophysiology of splanchnic organ inflammation. In addition, we discuss the limitations of the different approaches and present potential solutions for the continued improvement of these important animal models.


Asunto(s)
Enfermedades Autoinmunes/fisiopatología , Modelos Animales de Enfermedad , Enfermedad Injerto contra Huésped/fisiopatología , Inflamación/fisiopatología , Enfermedades Inflamatorias del Intestino/fisiopatología , Circulación Esplácnica , Animales , Enfermedades Autoinmunes/inmunología , Enfermedad Injerto contra Huésped/inmunología , Humanos , Inflamación/inmunología , Enfermedades Inflamatorias del Intestino/inmunología , Ratones
4.
Pathophysiology ; 30(4): 522-547, 2023 Nov 20.
Artículo en Inglés | MEDLINE | ID: mdl-37987308

RESUMEN

The objective of this study was to determine how housing temperature and genetic diversity affect the onset and severity of allogeneic T cell-induced tissue damage in mice subjected to reduced intensity conditioning (RIC). We found that adoptive transfer of allogeneic CD4+ T cells from inbred donors into sub-lethally irradiated inbred recipients (I→I) housed at standard housing temperatures (ST; 22-24 °C) induced extensive BM and spleen damage in the absence of injury to any other tissue. Although engraftment of T cells in RIC-treated mice housed at their thermo-neutral temperature (TNT; 30-32 °C) also developed similar BM and spleen damage, their survival was markedly and significantly increased when compared to their ST counterparts. In contrast, the adoptive transfer of allogeneic T cells into RIC-treated outbred CD1 recipients failed to induce disease in any tissue at ST or TNT. The lack of tissue damage was not due to defects in donor T cell trafficking to BM or spleen but was associated with the presence of large numbers of B cells and myeloid cells within these tissues that are known to contain immunosuppressive regulatory B cells and myeloid-derived suppressor cells. These data demonstrate, for the first time, that housing temperature affects the survival of RIC-treated I→I mice and that RIC-conditioned outbred mice are resistant to allogeneic T cell-induced BM and spleen damage.

5.
J Clin Invest ; 132(21)2022 11 01.
Artículo en Inglés | MEDLINE | ID: mdl-36074578

RESUMEN

Graft-versus-host disease (GVHD), manifesting as either acute (aGVHD) or chronic (cGVHD), presents significant life-threatening complications following allogeneic hematopoietic cell transplantation. Here, we investigated Friend virus leukemia integration 1 (Fli-1) in GVHD pathogenesis and validated Fli-1 as a therapeutic target. Using genetic approaches, we found that Fli-1 dynamically regulated different T cell subsets in allogeneic responses and pathogenicity in the development of aGVHD and cGVHD. Compared with homozygous Fli1-deficient or WT T cells, heterozygous Fli1-deficient T cells induced the mildest GVHD, as evidenced by the lowest Th1 and Th17 cell differentiation. Single-cell RNA-Seq analysis revealed that Fli-1 differentially regulated CD4+ and CD8+ T cell responses. Fli-1 promoted the transcription of Th1/Th17 pathways and T cell receptor-inducible (TCR-inducible) transcription factors in CD4+ T cells, while suppressing activation- and function-related gene pathways in CD8+ T cells. Importantly, a low dose of camptothecin, topotecan, or etoposide acted as a potent Fli-1 inhibitor and significantly attenuated GVHD severity, while preserving the graft-versus-leukemia (GVL) effect. This observation was extended to a xenograft model, in which GVHD was induced by human T cells. In conclusion, we provide evidence that Fli-1 plays a crucial role in alloreactive CD4+ T cell activation and differentiation and that targeting Fli-1 may be an attractive strategy for treating GVHD without compromising the GVL effect.


Asunto(s)
Enfermedad Injerto contra Huésped , Trasplante de Células Madre Hematopoyéticas , Leucemia , Linfocitos T , Humanos , Virus de la Leucemia Murina de Friend , Enfermedad Injerto contra Huésped/genética , Efecto Injerto vs Leucemia , Trasplante de Células Madre Hematopoyéticas/efectos adversos , Factores de Transcripción , Trasplante Homólogo/efectos adversos , Linfocitos T/inmunología
6.
Front Immunol ; 13: 936164, 2022.
Artículo en Inglés | MEDLINE | ID: mdl-35990658

RESUMEN

People living with HIV and who receive antiretroviral therapy have a significantly improved lifespan, compared to the early days without therapy. Unfortunately, persisting viral replication in the lungs sustains chronic inflammation, which may cause pulmonary vascular dysfunction and ultimate life-threatening Pulmonary Hypertension (PH). The mechanisms involved in the progression of HIV and PH remain unclear. The study of HIV-PH is limited due to the lack of tractable animal models that recapitulate infection and pathobiological aspects of PH. On one hand, mice with humanized immune systems (hu-mice) are highly relevant to HIV research but their suitability for HIV-PH research deserves investigation. On another hand, the Hypoxia-Sugen is a well-established model for experimental PH that combines hypoxia with the VEGF antagonist SU5416. To test the suitability of hu-mice, we combined HIV with either SU5416 or hypoxia. Using right heart catheterization, we found that combining HIV+SU5416 exacerbated PH. HIV infection increases human pro-inflammatory cytokines in the lungs, compared to uninfected mice. Histopathological examinations showed pulmonary vascular inflammation with arterial muscularization in HIV-PH. We also found an increase in endothelial-monocyte activating polypeptide II (EMAP II) when combining HIV+SU5416. Therefore, combinations of HIV with SU5416 or hypoxia recapitulate PH in hu-mice, creating well-suited models for infectious mechanistic pulmonary vascular research in small animals.


Asunto(s)
Infecciones por VIH , Hipertensión Pulmonar , Hipertensión Arterial Pulmonar , Animales , Infecciones por VIH/complicaciones , Humanos , Hipertensión Pulmonar/etiología , Hipoxia/patología , Sistema Inmunológico/patología , Inflamación/complicaciones , Ratones
7.
PLoS One ; 16(8): e0254845, 2021.
Artículo en Inglés | MEDLINE | ID: mdl-34358240

RESUMEN

BACKGROUND: Hematopoietic stem cell transplantation is a potential cure for certain life-threatening malignant and nonmalignant diseases. However, experimental and clinical studies have demonstrated that pre-transplant myeloablative conditioning damages the gut leading to translocation of intestinal bacteria and the development of acute graft vs. host disease (aGVHD). The overall objective of this study was to determine whether administration of broad spectrum antibiotics (Abx) affects the onset and/or severity of aGVHD in lymphopenic mice that were not subjected to toxic, pre-transplant conditioning. RESULTS: We found that treatment of NK cell-depleted recombination activating gene-1-deficient (-NK/RAG) recipients with an Abx cocktail containing vancomycin and neomycin for 7 days prior to and 4 weeks following adoptive transfer of allogeneic CD4+ T cells, exacerbated the development of aGVHD-induced BM failure and spleen damage when compared to untreated-NK/RAG recipients engrafted with syngeneic or allogeneic T cells. Abx-treated mice exhibited severe anemia and monocytopenia as well as marked reductions in BM- and spleen-residing immune cells. Blinded histopathological analysis confirmed that Abx-treated mice engrafted with allogeneic T cells suffered significantly more damage to the BM and spleen than did untreated mice engrafted with allogeneic T cells. Abx-induced exacerbation of BM and spleen damage correlated with a dramatic reduction in fecal bacterial diversity, marked loss of anaerobic bacteria and remarkable expansion of potentially pathogenic bacteria. CONCLUSIONS: We conclude that continuous Abx treatment may aggravate aGVHD-induced tissue damage by reducing short chain fatty acid-producing anaerobes (e.g. Clostridium, Blautia) and/or by promoting the expansion of pathobionts (e.g. Akkermansia) and opportunistic pathogens (Cronobacter).


Asunto(s)
Antibacterianos/uso terapéutico , Médula Ósea/patología , Progresión de la Enfermedad , Enfermedad Injerto contra Huésped/tratamiento farmacológico , Linfopenia/tratamiento farmacológico , Bazo/patología , Enfermedad Aguda , Traslado Adoptivo , Animales , Antibacterianos/farmacología , Bacterias/clasificación , Bacterias/efectos de los fármacos , Bacterias/crecimiento & desarrollo , Recuento de Células Sanguíneas , Médula Ósea/efectos de los fármacos , Linfocitos T CD4-Positivos/inmunología , Linfocitos T CD4-Positivos/microbiología , Citocinas/sangre , Heces/microbiología , Enfermedad Injerto contra Huésped/sangre , Enfermedad Injerto contra Huésped/complicaciones , Enfermedad Injerto contra Huésped/patología , Inflamación/sangre , Inflamación/complicaciones , Inflamación/patología , Linfopenia/sangre , Linfopenia/complicaciones , Masculino , Ratones , Filogenia , Bazo/efectos de los fármacos , Trasplante Homólogo
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