scholarly journals Mismatch in Sirpα, a Regulatory Protein in Innate Immunity, Is Associated with Outcomes of Allogeneic Stem Cell Transplantation for Lymphoid Malignancies

Blood ◽  
2021 ◽  
Vol 138 (Supplement 1) ◽  
pp. 1804-1804
Author(s):  
Rima M. Saliba ◽  
Uri Greenbaum ◽  
Qing Ma ◽  
Samer A. Srour ◽  
Gabriela Rondon ◽  
...  
Keyword(s):  
Innate Immunity ◽  
Stem Cell ◽  
Immune System ◽  
Acute Gvhd ◽  
Lymphoblastic Leukemia ◽  
Regulatory Protein ◽  
Innate Immune ◽  
Lymphoid Malignancies ◽  
Related Donor

Abstract Allogeneic hematopoietic stem cell transplantation (allo-HSCT) is a potentially curative therapy for patients with hematologic malignancies. It is conventionally believed that alloreactivity is initiated by T-cells recognizing the non-self HLA molecules on the graft. Cells from the innate immune system, such as macrophages and monocytes, are induced by nonspecific "danger" molecules released from damaged tissue. Recent studies revealed that the innate immune system could distinguish the non-self graft and subsequently prime the adaptive immune system to advance the allorecognition process. Signal regulatory protein α (SIRPα) is an immunoglobulin superfamily receptor that is expressed on macrophages and myeloid cells. The interaction between SIRPα and its ubiquitously expressed ligand, CD47, suppresses the macrophages phagocytic function. It has been demonstrated that recipient's monocytes detect polymorphism in SIRPα, and mismatches of SIRPα between donor and recipient can regulate the allorecognition response in the murine model. Our group has recently investigated the role of SIRPα variant mismatch in recipients of allo-HSCT from an HLA-matched related donor for treatment of acute myeloid leukemia (AML) or myelodysplastic syndrome (MDS). We found that donor/recipient SIRPα mismatch was commonly detected in 39% of transplant pairs, and the presence of the mismatch was significantly associated with an increase rate of chronic graft-versus-host disease (cGvHD) and a lower rate of early relapse. We hypothesized that comparable effects could be occurring in recipients of allo-HSCT for treatment of lymphoid malignancies. We tested our hypothesis in a cohort of patients who received an allo-HSCT from an HLA matched-related donor at our institution between January 2008 and December 2018 for the treatment of lymphoid malignancies. Only patients who received a peripheral blood stem cell graft and tacrolimus/methotrexate for GvHD prophylaxis were eligible for the study. A total of 313 patients met the eligibility criteria including 310 (99%) who engrafted and 3 (1%) who died early before engraftment. The risk of early death was not associated with SIRPα mismatch variant. Only patients who engrafted (N=310) were included in subsequent analyses. Among these, 42% (N=130) of donor/recipient pairs were SIRPα mismatched. The majority of patients were treated for acute lymphoblastic leukemia (N=115, 37%) or non-Hodgkin's lymphoma (NHL) (N=114, 37%), followed by chronic lymphoblastic leukemia (N=59, 19%), and Hodgkin's lymphoma (N=22, 7%). Most (N=259, 84%) of patients had chemo-sensitive disease. The median age at transplant was 51 (range: 18-72) years, and 64% of patients were female. The median age of donors was 50 (range: 18-79) years and 53% were male. Conditioning regimens were myeloablative in 52% of cases. Outcomes were evaluated accounting for competing risks. The median follow-up in surviving patients was 74 (range: 3-124) months. A total of 99, 84, 108, and 51 patients experienced grade 2-4 acute GvHD, cGvHD requiring systemic immunosuppressive therapy, disease progression, and non-relapse mortality (NRM), respectively. Multivariate analyses showed that SIRPα mismatch was associated with a significantly higher rate (hazard ratio [HR]=1.9, P=.005) of cGvHD requiring systemic immunosuppressive therapy, and a lower rate (HR=.5, P=.004) of disease progression. Notably, the increased rate of cGVHD was consistent across the 4 lymphoid malignancies evaluated, yet the lower rate of relapse was observed in all diagnoses except NHL. There was no significant impact of SIRPα mismatch on grade 2-4 acute GvHD (HR=1.2, P=.3) or on NRM (HR=0.7, P=.3). Consistent with our preceding study in the AML/MDS cohort, the mismatch in SIRPα, a regulatory protein in innate immunity, is associated with a higher rate of cGvHD and relapse protection in patients who underwent allo-HSCT for lymphoid malignancies. The results of this study could be clinically important in donor selection and provide insight into the underlying role of innate immunity in allo-HSCT. Disclosures Shpall: Adaptimmune: Consultancy; Takeda: Patents & Royalties; Novartis: Consultancy; Magenta: Honoraria; Navan: Consultancy; Bayer HealthCare Pharmaceuticals: Honoraria; Magenta: Consultancy; Axio: Consultancy; Affimed: Patents & Royalties; Novartis: Honoraria.

scholarly journals Toll-like receptor-mediated innate immunity against herpesviridae infection: a current perspective on viral infection signaling pathways

2020 ◽  
Vol 17 (1) ◽  
Author(s):  
Wenjin Zheng ◽  
Qing Xu ◽  
Yiyuan Zhang ◽  
Xiaofei E ◽  
Wei Gao ◽  
...  
Keyword(s):  
Innate Immunity ◽  
Immune System ◽  
Signaling Pathways ◽  
Critical Role ◽  
Innate Immune ◽  
Host Cells ◽  
Main Body ◽  
Current Perspective ◽  
Viral Components

Abstract Background In the past decades, researchers have demonstrated the critical role of Toll-like receptors (TLRs) in the innate immune system. They recognize viral components and trigger immune signal cascades to subsequently promote the activation of the immune system. Main body Herpesviridae family members trigger TLRs to elicit cytokines in the process of infection to activate antiviral innate immune responses in host cells. This review aims to clarify the role of TLRs in the innate immunity defense against herpesviridae, and systematically describes the processes of TLR actions and herpesviridae recognition as well as the signal transduction pathways involved. Conclusions Future studies of the interactions between TLRs and herpesviridae infections, especially the subsequent signaling pathways, will not only contribute to the planning of effective antiviral therapies but also provide new molecular targets for the development of antiviral drugs.

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.

TLR9 but Not NOD2/CARD15 Gene Polymorphism Influence Outcome in AML-Patients Transplanted From HLA-Identical Sibling Donors.

Blood ◽  
2009 ◽  
Vol 114 (22) ◽  
pp. 1191-1191
Author(s):  
Ahmet H Elmaagacli ◽  
Michael Koldehoff ◽  
Tania Gromke ◽  
Nina K Steckel ◽  
Dietrich W. Beelen
Keyword(s):  
Overall Survival ◽  
Immune System ◽  
Gene Polymorphism ◽  
Acute Gvhd ◽  
Innate Immune ◽  
Gene Variants ◽  
Gene Variant ◽  
Donor Side ◽  
Tlr9 Gene

Abstract Abstract 1191 Poster Board I-213 Background. We evaluated in a homogenous group of 101 AML-patients after non-T-cell depleted, myeloablative transplantation from HLA-identical sibling donors the role of gene polymorphism of TLR1, TLR4,TLR9, IL23R, and NOD2 on the outcome of transplant. TLR9 and NOD2 are part of the innate immune system, which are able to recognize and bind to the so-called pathogen-associated molecular patterns (PAMPs) from invading pathogens. They induce a rapid innate immune response to microbial invaders and thereby also an activation of the adoptive immune system. TLR9 is activated by DNA containing unmethylated CpG motifs and produces potent Th1-type innate and adaptive immune responses. NOD2 was reported to influence the outcome of transplant. Methods. Here we evaluated the genotype of 101 AML-patients with their donors for the occurrence of the TLR1, TLR4 (A1063G and C1363T), TLR9 (T1237C and T1486C), IL23R (G1142A) and NOD2 by real-time PCR who underwent allogeneic transplantation. Results. Gene variants of the NOD2 gene at patients and donors side were observed in 8.8% of the patients. The CC gene variant of TLR9 -1486 occurred in 19.1% of patients. In our retrospective analyzed study we found that the TLR9 gene variant was the only polymorphism that influenced the outcome of transplant. The estimate for 5-year overall survival (OS) in patients with the CC gene variant of TLR9 at (T1486C) was 74.6% ± 11.1% compared to 45.2% ± 6.0% (p<0.01) in patients with TC/TT of TLR9 gene variants. No influence on 5-year OS was seen for gene polymorphisms of NOD2 or IL23R in this study group. Patients with TLR9 CC gene variant at 1486 or NOD2 gene variants (at recipient and donor side) had a lower rate of leukemic relapse at 5-year post transplant 24.6% ±10.4% versus 44.4 ± 6.6% for TLR9 [p<0.10], and 25% ± 15.3% versus 39.7% ± 7.7% NS). 5-year TRM was lowest in patients with CC gene variant of TLR9 with 7.7% versus 23.7%. Surprisingly also patients with NOD2 gene variant at donor and recipient side hade a reduced 5-year TRM compared to patients with wild-type of NOD2. Acute GVHD grade 2-4 was higher (although not significant) in patients with NOD2 gene variants (recipient and donor side) with 57.1% versus 39.3%. In contrast to NOD2, patients with the gene variant of TLR9 had a no difference in the incidence of acute GVHD grade 2-4 with 22.8% versus 33.1% demonstrating that the lower estimate for relapse risk in patient with TLR9 gene variant was not associated with increased GVHD. Conclusions. The results presented here suggest that the CC gene variant of TLR at 1483 is a strong marker for outcome of transplant, whereas NOD2 gene variants had no influence on the overall survival. The role of NOD2 in transplant must be further evaluated. The gene variant of TLR9 might be helpful in patients planning a transplant as a prognostic positive factor. Disclosures. No relevant conflicts of interest to declare.

scholarly journals Myeloid cells, tissue homeostasis, and anatomical barriers as innate immune effectors in arterial hypertension

2021 ◽  
Vol 99 (3) ◽  
pp. 315-326
Author(s):  
Johannes Wild ◽  
Philip Wenzel
Keyword(s):  
Innate Immunity ◽  
Immune System ◽  
Arterial Hypertension ◽  
Myeloid Cells ◽  
Tissue Homeostasis ◽  
Innate Immune ◽  
Complete Understanding ◽  
Key Drivers ◽  
Hinge Points

AbstractAlthough essential hypertension affects a large proportion of the human population and is one of the key drivers of cardiovascular mortality worldwide, we still do not have a complete understanding of its pathophysiology. More than 50 years ago, the immune system has been identified as an important part of the pathogenesis of arterial hypertension. An exceeding variety of recent publications deals with the interplay between the numerous different components of the immune system and mechanisms of arterial hypertension and has substantially contributed to our understanding of the role of immunity and inflammation in the pathogenesis of the disease. In this review, we focus on myeloid cells and anatomical barriers as particular aspects of innate immunity in arterial hypertension. Since it represents a first line of defense protecting against pathogens and maintaining tissue homeostasis, innate immunity provides many mechanistic hinge points in the area of hypertension.

Role of Innate Immune System in Environmental Lung Diseases

2021 ◽  
Vol 21 (5) ◽  
Author(s):  
Marissa A. Guttenberg ◽  
Aaron T. Vose ◽  
Robert M. Tighe
Keyword(s):  
Immune System ◽  
Innate Immune System ◽  
Lung Diseases ◽  
Innate Immune
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