scholarly journals Interferon Gamma, a Link between Hemophagocytic Lymphohistiocytosis and Dengue Fever Virus: A Literature Review of a Shared Inflammatory Pathway Resulting in Cytopenias and Potential Future Treatment Directions

Blood ◽  
2019 ◽  
Vol 134 (Supplement_1) ◽  
pp. 4869-4869 ◽  
Author(s):  
Darla K Liles ◽  
Heather Brody ◽  
Juan Alvarez Posada ◽  
Karim Hebishi ◽  
John Thiele
Keyword(s):  
Clinical Trial ◽  
Bone Marrow ◽  
Immune System ◽  
Natural Killer ◽  
Dengue Fever ◽  
Sickle Cell ◽  
Innate Immune System ◽  
Lymphoproliferative Disorder ◽  
Innate Immune ◽  
Travel History

Our patient was an elderly female, previously healthy, who presented with fever, anemia, thrombocytopenia, and enlarged spleen. Her complaints were progressive over the course of two months. She was treated with antibiotics with no improvement. Underlying lymphoproliferative disorder was suspected, and a bone marrow biopsy and aspiration was completed. While there was no evidence for lymphoproliferative disorder, there was hemophagocytosis. Further evaluation revealed ferritin 1,151 ng/mL, soluble IL2 receptor 32,186 u/mL, and natural killer activity was low. She was diagnosed with secondary hemophagocytic lymphohistiocytosis (HLH). During her evaluation, her condition acutely worsened; she became encephalopathic with hypotension requiring vasopressor support and respiratory failure. The patient was given etoposide with rapid improvement in overall clinical status though further cytopenias secondary to etoposide prevented further treatment. She was ultimately diagnosed with Dengue Fever Virus by IgM Antibody, 4.54, with positive result >/= 2.84. A positive result is highly suggestive of acute disease, though cross reactivity is possible with other flavi viruses. The result was confirmed. The patient lived in a rural community in Eastern NC and had no travel history; the diagnosis was reported to the North Carolina public health department and the Center for Disease Control. Despite recognition and treatment of the HLH and Dengue fever, the patient died of complications. Both Dengue Fever and HLH cause significant morbidity and mortality. Their disease courses, while unique, do have some interesting parallels. They both can be associated with significant suppression of bone marrow function, frequently being associated with cytopenias. This is a major source of morbidity in both disease states. While Dengue Fever is a known, though rare, cause of HLH, it has not previously been reported in the continental United States. In this case report, we examine the known cytokine pathway activations in each disease state and their commonalities, focusing on bone marrow suppressive cytokines and subsequently suggesting mechanisms for targeted treatment of HLH. Even with our best treatments, in HLH, the associated mortality among all causes is around 42%. The mortality for untreated severe dengue is as high as 20% though with appropriate care, that is much improved at 1-2%. In HLH and Dengue, IL-1B, IFN-Ƴ, IL6, and TNF-α are increased. A common cytokine, IFN-Ƴ, directly affects bone marrow activity and can alter hematopoiesis. IFN-Ƴ is directly implicated in several bone marrow failure syndromes making it an attractive target to modulate. Based on results of an in vitro study of CD34+ hematopoietic stem cells (HSC) in the presence and absence of IFN-Ƴ in differing concentrations, IFN-Ƴ inhibited the ability of HSC to repopulate themselves though it did not affect their ability to differentiate. This was also shown in vivo in a mouse HSC transplant model with mirroring results. In our patient, it follows logical and chronological progression that her cytopenias worsened over time as her pool of CD34+ HSC was depleted. Additional studies of IFN-Ƴ and hematopoiesis suggest that IFN-Ƴ directly negatively affects the supportive bone marrow mesenchymal stoma cells which provide the cytokine environment that supports HSC repopulation. IFN-Ƴ is produced from the innate immune system via dendritic cells, natural killer (NK), and natural killer T (NKT) cell and in the adaptive immune system via Th1 T lymphocytes. IFN-Ƴ is a major activator of macrophages which in turn are responsible for secreting multiple other pro-inflammatory cytokines as previously mentioned. In Dengue, the innate immune system is activated via macrophage and dendritic cells. In HLH, IFN-Ƴ is primarily produced by T-cells. IFN-Ƴ is known to stimulate the janus kinase-STAT (JAK-STAT) signaling pathway in macrophages to increase inflammation. We suggest that modulation of the cytokines directly involved in the inflammatory syndrome might be considered. In summary, we report a case of Dengue fever with associated secondary HLH. This is the first report of Dengue fever in the continental United States in a person without travel history. In addition, this case report highlights the commonalities of the immune activation seen in both Dengue fever as well as secondary HLH and may indicate the potential for more targeted immunomodulation. Disclosures Liles: Imara: Other: PI on Clinical trial- Sickle cell ; Novartis: Other: PI on clinical trial Sickle cell ; Shire: Other: PI on clinical trial Sickle cell .

A Critical Role for Innate Immunity In Allogeneic Hematopoietic Cell Rejection Via the TLR4/TRIF Pathway

Blood ◽  
2010 ◽  
Vol 116 (21) ◽  
pp. 77-77
Author(s):  
Hong Xu ◽  
Jun Yan ◽  
Ziqiang Zhu ◽  
Yiming Huang ◽  
Yujie Wen ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Innate Immunity ◽  
T Cells ◽  
Immune System ◽  
T Cell ◽  
Innate Immune System ◽  
Critical Role ◽  
Innate Immune ◽  
Wild Type

Abstract Abstract 77 Adaptive immunity, especially T cells, has long been believed to be the dominant immune barrier in allogeneic transplantation. Targeting host T cells significantly reduces conditioning for bone marrow cell (BMC) engraftment. Innate immunity has been recently shown to pose a significant barrier in solid organ transplantation, but has not been addressed in bone marrow transplantation (BMT). Using T cell deficient (TCR-β/δ−/−) or T and B cell deficient (Rag−/−) mice, we found that allogeneic BMC rejection occurred early before the time required for T cell activation and was T- and B-cell independent, suggesting an effector role for innate immune cells in BMC rejection. Therefore, we hypothesized that by controlling both innate and adaptive immunity, the donor BMC would have a window of advantage to engraft. Survival of BMC in vivo was significantly improved by depleting recipient macrophages and/or NK cells, but not neutrophils. Moreover, depletion of macrophages and NK cells in combination with co-stimulatory blockade with anti-CD154 and rapamycin as a novel form of conditioning resulted in 100% allogeneic engraftment without any irradiation and T cell depletion. Donor chimerism remained stable and durable up to 6 months. Moreover, specific Vβ5½ and Vβ11 clonal deletion was detected in host CD4+ T cells in chimeras, indicating central tolerance to donor alloantigens. Whether and how the innate immune system recognizes or responds to allogeneic BMCs remains unknown. Toll-like receptors (TLRs) are a class of proteins that play a key role in the innate immune system. The signaling function of TLR depends on intracellular adaptors. The adaptor MyD88 transmits signals emanating from all TLR, except TLR3 while TRIF specifically mediates TLR3 and TLR4 signaling via type 1 IFN. To further determine the innate signaling pathways in allogeneic BMC rejection, B6 background (H2b) MyD88−/− and TRIF−/− mice were conditioned with anti-CD154/rapamycin plus 100 cGy total body irradiation and transplanted with 15 × 106 BALB/c (H2d) BMC. Only 33.3% of MyD88−/− recipients engrafted at 1 month, resembling outcomes for wild-type B6 mice. In contrast, 100% of TRIF−/− mice engrafted. The level of donor chimerism in TRIF−/− mice was 5.1 ± 0.6% at one month, significantly higher than in MyD88−/− and wild-type B6 controls (P < 0.005). To determine the mechanism of innate signaling in BMC rejection, we examined whether TRIF linked TLR3 or TLR4 is the key pattern recognition receptor involved in BMC recognition. To this end, TLR3−/− and TLR4−/− mice were transplanted with BALB/c BMC with same conditioning. None of the TLR3−/− mice engrafted. In contrast, engraftment was achieved in 100% of TLR4−/− mice up to 6 months follow up. Taken together, these results suggest that rejection of allogeneic BMC is uniquely dependent on the TLR4/TRIF signaling pathway. Thus, our results clearly demonstrate a previously unappreciated role for innate immunity in allogeneic BMC rejection. Our current findings are distinct from prior reports demonstrating a critical role of MyD88 in rejection of allogeneic skin grafts and lung, and may reflect unique features related to BMC. The findings of the role of innate immunity in BMC rejection would lead to revolutionary changes in our understanding and management of BMT. This would be informative in design of more specific innate immune targeted conditioning proposals in BMT to avoid the toxicity. Disclosures: Bozulic: Regenerex LLC: Employment. Ildstad:Regenerex LLC: Equity Ownership.

Innate Immunity Is Responsible for Early Allorejection of Donor Bone Marrow Cells.

Blood ◽  
2009 ◽  
Vol 114 (22) ◽  
pp. 3523-3523
Author(s):  
Hong Xu ◽  
Jun Yan ◽  
Ziqiang Zhu ◽  
Lala-Rukh Hussain ◽  
Yiming Huang ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Innate Immunity ◽  
Immune System ◽  
T Cell ◽  
Innate Immune System ◽  
Immune Cell ◽  
Marrow Cell ◽  
Donor Cell ◽  
Innate Immune ◽  
Kinetics Of

Abstract Abstract 3523 Poster Board III-460 Adaptive immunity, especially T cells, has long been believed to be the dominant immune response in allogeneic transplantation. However, innate immunity has been recently shown to pose a significant barrier to the induction of tolerance to solid organ transplants. The role of the innate immune system in bone marrow cell alloreactivity has not been addressed. The innate immune system provides the first line of defense in the removal of pathogens because of the delay in generation of adaptive immune responses. Our present findings show that innate immunity is a significant first line barrier in bone marrow cell (BMC) rejection. To determine the effect of innate immune cell populations on rejection of donor BMCs, T cell deficient mice (TCR β/δ−/−) were used as BMC recipients in in vivo cytotoxicity assays (Figure A). TCRβ/δ−/− mice have normal innate immune cell populations but do not initiate adaptive cell-mediated cytotoxic or humoral responses. 20 × 106 CFSE labeled donor (high CFSE fluorescence intensity) and recipient control splenocytes (low CFSE fluorescence intensity) were injected into TCRβ/δ−/− and wildtype control B6 recipient mice. Donor cell survival was compared over time. Donor BALB/c splenocytes were eliminated in wildtype B6, with rejection complete by day 3. The kinetics of elimination of donor cells in TCRβ/δ−/− mice was similar to that for wildtype B6 controls, with donor cells eliminated by day 3. These results indicate that early rejection of the splenocytes in wildtype mice was T cell-independent. The acute rejection of BMC in wildtype B6 recipients occurred within 3 days, which is prior to the time required for T cell activation. Thus the effectors mediating BMC rejection would be the innate immune cells: macrophages, neutrophils, or NK cells. To rule out potential involvement of natural Abs in the cytotoxicity we observed in the TCRβ/δ−/− mice, Rag−/− mice were used as recipients (Figure B). Rag−/− mice do not produce mature T cells or B cells. 20 × 106 CFSE labeled donor (high CFSE intensity) and recipient control BM cells (low CFSE intensity) were injected into Rag−/−mice. Rag−/− and wildtype B6 control mice exhibited similar kinetics of donor cell cytolysis. The rapid elimination of allogeneic cells from immunocompetent mice is comparable with that observed in T cell- (TCRβ/δ−/−) or T and B cell- (Rag−/−) deficient mice indicates that allogeneic cells are subject to T cell-independent rejection at the early time period after cell infusion (≤ 3 days). As the kinetics of cytotoxicity were similar in experiments using either splenocytes or BMCs as target cells in our later experiments, our data suggest that the innate immune system is responsible for early allorejection of donor BMC at the early inductive period for adaptive immunity. These findings may have significant impact on the development of immune-based nonmyeloablative conditioning strategies and show for the first time that a dominant factor in BMC rejection is contributed by innate immune responses. Disclosures: Bozulic: Regenerex: Employment. Ildstad:Regenerex: Equity Ownership.

Trial-in-progress: A pilot study of combined immune checkpoint inhibition in combination with ablative therapies in subjects with hepatocellular carcinoma (HCC).

2021 ◽  
Vol 39 (3_suppl) ◽  
pp. TPS355-TPS355
Author(s):  
Hailey Kathryn Carroll ◽  
Umair Aleem ◽  
Pooja Varghese ◽  
Marie Galligan ◽  
Michele Bourke ◽  
...  
Keyword(s):  
Hepatocellular Carcinoma ◽  
Immune Response ◽  
Immune System ◽  
Pilot Study ◽  
Natural Killer Cells ◽  
Natural Killer ◽  
Immune Checkpoint ◽  
Innate Immune System ◽  
Innate Immune

TPS355 Background: Locoregional therapies for hepatocellular carcinoma, such as transcatheter arterial chemoembolization (TACE) or ablation, can induce a peripheral anti-tumor immune response. This may be amplified by immune checkpoint inhibitors (ICI). Early and higher anti-CTLA4 dosing could potentially lead to better priming and a stronger immune response. Recent data has suggested that early (day 1 only), increased doses of anti-CTLA4 therapy, was associated with encouraging clinical activity and a tolerable safety profile. This study will evaluate dual immune checkpoint, CTLA4 (tremelimumab, day 1-only dosing) and PD-L1 (durvalumab) blockade in combination with TACE in patients with advanced HCC. Intensive peripheral immune-monitoring and longitudinal on-treatment tumor biopsies will focus on the role of the innate immune system, particularly Natural Killer cells, in anti-tumor responses. Methods: Patients with HCC (Childs Pugh A/B7; Barcelona Clinic Liver Cancer Stage B/C; ECOG 0/1; sorafenib-naïve or experienced) are being enrolled in a pilot study (Study Number UCDCRC/19/01) of tremelimumab at 2 dose levels (DL1 and DL2) in combination with durvalumab and TACE until disease progression (per irRECIST). DL1: tremelimumab (75mg q28 days for 4 doses) and durvalumab (1500mg q28 days). DL2: tremelimumab (300mg in a single dose on day 1) and durvalumab (1500mg q28 days). Subtotal TACE will be performed during study week 6 with the dose-limiting toxicity (DLT) evaluation period encompassing the first 8 weeks of the study. Primary endpoint is 6-month progression-free survival with secondary efficacy endpoints being safety, tolerability and overall survival. Exploratory objectives will evaluate changes in immune parameters in the tumor and peripheral blood of patients undergoing anti-CTLA4 therapy pre- and post-RFA or TACE. A major focus will be on the role of the innate immune system, particularly Natural Killer cells, in anti-tumor responses. Patients will be enrolled and treated at St Vincent’s University Hospital in Dublin, Ireland. This study is currently open and actively recruiting. Clinical trial information: EudraCT Number 2019-002767-98.

A “Loss-of-Tolerance” Phenotype of the Liver Macrophage System to LPS Induces Overwhelming Systemic Inflammation and Early Death in a Knockout-Transgenic Mouse Model of Sickle Cell Disease.

Blood ◽  
2005 ◽  
Vol 106 (11) ◽  
pp. 2337-2337
Author(s):  
Steffen E. Meiler ◽  
Ilka Theruvath ◽  
Marlene Wade ◽  
C. Alvin Head
Keyword(s):  
Immune Response ◽  
Immune System ◽  
Sickle Cell Disease ◽  
Sickle Cell ◽  
Innate Immune System ◽  
Innate Immune ◽  
Cell Disease ◽  
Liver Macrophage ◽  
Tnf Α

Abstract Infections and death from fulminant sepsis remain a constant threat to patients with sickle cell disease (SCD). Established explanations include an impaired ability to contain and eliminate pathogenic organisms due to defects in spleen function and adaptive immunity. To the contrary, very little is known about the “first-line” response of the innate immune system after contact with pathogen associated cell components. An escalated immune (inflammatory) response to microbial structures would provide an alternative mechanism to explain increased rates of infectious complications and septic death in sickle cell patients. To test this hypothesis, knockout-transgenic mice homozygous for the human β-sickle globin gene (SS) were treated with a low dose of the canonical infectious stimulus lipopolysaccharide (0.5 μg/g bw; i.p.; 22°C) and compared to heterozygous sickle trait (ST) and C57BL/6 animals. Phenotypically, sickle mice appeared much sicker after LPS and displayed strict seclusion behavior, cessation of food intake, and physiological signs of stress. Body core (rectal) temperature decreased precipitously and irreversibly in sickle animals (~12°C/8hrs vs. ~2°C/8hrs [ST and C57BL/6]) followed by rapid death (50%/12h; 100%/48h vs 0% [ST; C57BL/6]). Analysis of the LD50 demonstrated an ~500-fold increased sensitivity to LPS in sickle mice (0.05 μg/g vs 25 μg/g [ST]). Serum cytokines (TNF-α, IL-6) were dramatically up-regulated in SS mice compared to control (TNF-α: 16-fold/2 hr post LPS, 100-fold/3 hr post LPS). Organ-specific immunohistochemical analysis of the marker cytokine TNF-α in liver, bone marrow, spleen, lung, and kidney four hrs after LPS revealed an astonishingly super-induced expression in the liver of sickle animals compared to controls. The liver of sickle animals showed several areas of coagulative liver necrosis unrelated to LPS and consistent with ischemic injury from recurrent sickle-mediated vascular occlusion. Immunoreactivity to TNF-α was most pronounced in areas of liver injury and mostly restricted to large macrophages (F4/80 +) surrounded by a T-lymphocytic (CD3+) infiltrate. In vitro analysis of Kupffer cells to serial concentrations of LPS recapitulated the in vivo results, demonstrating up to 20-fold larger TNF-α levels in cells derived from sickle livers. To further elucidate the role of the liver macrophage in the in vivo immune response to LPS, sickle animals were challenged with LPS forty-eight hrs after Kupffer cell depletion with Gadolinium Chloride. Sickle mice treated with Gadolinium experienced enhanced survival and an ~90% reduction in serum TNF-α levels. In summary, the present study offers new insights into the responsiveness of the innate immune system in SCD to the highly conserved bacterial cell component, lipopolysaccharide. Unexpectedly, these data suggest that the liver macrophage in SCD, typically a cell type tolerant to the pro-inflammatory effects of LPS, has a cardinal role in orchestrating an excessive and harmful innate immune response to bacterial infections. Further studies will have to determine the immune response to other conserved bacterial structures and relate these findings to the human form of SCD.

The role of Natural killer (NK) cells as APCs, Cytotoxicity, Immuno-regulatory in Innate and Adaptive immune as Potential Therapeutic and Preventive Target in Infectious Diseases

2021 ◽  
Vol 12 (04) ◽  
pp. 415-437
Author(s):  
Dr. Zelalem Kiros Bitsue
Keyword(s):  
Immune System ◽  
Nk Cells ◽  
Natural Killer ◽  
Host Defense ◽  
Immune Regulation ◽  
Innate Immune System ◽  
Adaptive Immune System ◽  
Innate Immune ◽  
Adaptive Immune

Natural killer (NK) cells are lymphocytes of the innate immune system that are critical in host defense and immune regulation. They are activated or inhibited through the ligation of germline-encoded receptors and are involved in mediating cytotoxicity, in producing cytokines and in providing co-stimulation to cells of the adaptive immune system.

The Innate Immune System and Cardiovascular Disease in ESKD: Monocytes and Natural Killer Cells

2020 ◽  
Vol 19 (1) ◽  
pp. 63-76 ◽  
Author(s):  
Evangelia Dounousi ◽  
Anila Duni ◽  
Katerina K. Naka ◽  
Georgios Vartholomatos ◽  
Carmine Zoccali
Keyword(s):  
Heart Failure ◽  
Cardiovascular Disease ◽  
Immune System ◽  
Kidney Disease ◽  
Nk Cells ◽  
Natural Killer ◽  
Innate Immune System ◽  
Nkt Cells ◽  
Innate Immune ◽  
Monocyte Subsets

Adverse innate immune responses have been implicated in several disease processes, including cardiovascular disease (CVD) and chronic kidney disease (CKD). The monocyte subsets natural killer (NK) cells and natural killer T (NKT) cells are involved in innate immunity. Monocytes subsets are key in atherogenesis and the inflammatory cascade occurring in heart failure. Upregulated activity and counts of proinflammatory CD16+ monocyte subsets are associated with clinical indices of atherosclerosis, heart failure syndromes and CKD. Advanced CKD is a complex state of persistent systemic inflammation characterized by elevated expression of proinflammatory and pro-atherogenic CD14++CD16+ monocytes, which are associated with cardiovascular events and death both in the general population and among patients with CKD. Diminished NK cells and NKT cells counts and aberrant activity are observed in both coronary artery disease and end-stage kidney disease. However, evidence of the roles of NK cells and NKT cells in atherogenesis in advanced CKD is circumstantial and remains to be clarified. This review describes the available evidence regarding the roles of specific immune cell subsets in the pathogenesis of CVD in patients with CKD. Future research is expected to further uncover the links between CKD associated innate immune system dysregulation and accelerated CVD and will ideally be translated into therapeutic targets.

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