Immunopathological characteristics of coronavirus disease 2019 cases in Guangzhou, China

SummaryCoronavirus disease 2019 (COVID-19) is a respiratory disorder caused by the highly contagious SARS-CoV-2. The immunopathological characteristics of COVID-19 patients, either systemic or local, have not been thoroughly studied. In the present study, we analyzed both the changes in the cellularity of various immune cell types as well as cytokines important for immune reactions and inflammation. Our data indicate that patients with severe COVID-19 exhibited an overall decline of lymphocytes including CD4+ and CD8+ T cells, B cells, and NK cells. The number of immunosuppressive regulatory T cells was moderately increased in patients with mild COVID-19. IL-2, IL-6, and IL-10 were remarkably up-regulated in patients with severe COVID-19. The levels of IL-2 and IL-6 relative to the length of hospital stay underwent a similar “rise-decline”pattern, probably reflecting the therapeutic effect. In conclusion, our study shows that the comprehensive decrease of lymphocytes, and the elevation of IL-2 and IL-6 are reliable indicators of severe COVID-19.

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Immunosuppressive milieu of high-risk localized prostate cancer.

Journal of Clinical Oncology ◽

10.1200/jco.2020.38.6_suppl.344 ◽

2020 ◽

Vol 38 (6_suppl) ◽

pp. 344-344

Author(s):

Victor Ricardo Adorno Febles ◽

Dennis Adeegbe ◽

Aarif Ahsan ◽

Jiansheng Wu ◽

Alireza Khodadad-Jamayran ◽

...

Keyword(s):

Prostate Cancer ◽

T Cells ◽

Regulatory T Cells ◽

Cd8 T Cells ◽

Peripheral Blood ◽

Immune Cell ◽

Histological Grade ◽

Statistical Significance ◽

Cell Types ◽

Localized Prostate Cancer

344 Background: The immune factors that modulate the aggressiveness of localized treatment-naïve prostate cancer remain poorly understood. Methods: Fresh tumor and peripheral blood were collected at the time of radical prostatectomy in patients with localized prostate cancer. We evaluated the immune cell composition of 22 patient samples employing multi-parametric flow cytometry. Samples were grouped by histological grade into intermediate (INTPCA) and high-grade (HIGHPCA) prostate cancers based on standard NCCN criteria and immune cell abundances were quantified by mean +/- SEM. Statistical significance was assessed using the Mann-Whitney test. Results: INTPCA and HIGHPCA tumors harbored a similar increase in CD8+ T cells ( p < 0.0005 and p < 0.05, respectively) and CD11b+CD68-CD16+ myeloid-derived cells (p < 0.05) relative to the peripheral blood. Other cell types were similarly decreased in both INTPCA and HIGHPCA, including CD11b+CD68+CD14+ ( p < 0.005 and p < 0.05, respectively). By contrast, regulatory T cells were the only cell type in our analysis to be uniquely enriched in HIGHPCA rather than INTPCA ( p < 0.05). The most unique feature found in phenotypic profiling of the immune repertoire of HIGHPCA relative to INTPCA was an increase in the immune inhibitory receptor ligand, PD-L1, in the tumor associated macrophages (CD11b+CD68+CD14+) compared to the periphery (p < 0.05). Conclusions: Collectively, our findings reveal that HIGHPCA harbors a distinct immunological landscape. Although effector CD8+ T cells are preferentially expressed in the tumor, these are met with an increased proportion of regulatory T cells as well as PD-L1 expressing macrophages that contribute to the inert tumor microenvironment. These are key features of aggressive prostate cancer that may serve as potential biomarkers and therapeutic targets.

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Resistance of Natural Killer and T Cells to Venetoclax Allows for Combination Treatment with Cancer Immunotherapy Agents

Blood ◽

10.1182/blood-2018-99-116405 ◽

2018 ◽

Vol 132 (Supplement 1) ◽

pp. 1118-1118 ◽

Cited By ~ 2

Author(s):

Elisabeth A Lasater ◽

An D Do ◽

Luciana Burton ◽

Yijin Li ◽

Erin Williams ◽

...

Keyword(s):

T Cells ◽

T Cell ◽

B Cells ◽

Nk Cells ◽

Cd8 T Cells ◽

Cd4 T Cells ◽

Immune Cell ◽

Single Agent ◽

Employment Equity ◽

Equity Ownership

Abstract Introduction: Intrinsic apoptosis is regulated by the BCL-2 family of proteins, which consists of both anti-apoptotic (BCL-2, BCL-XL, MCL-1) and pro-apoptotic (BIM, BAX, BAK, BAD) proteins. Interaction between these proteins, as well as stringent regulation of their expression, mediates cell survival and can rapidly induce cell death. A shift in balance and overexpression of anti-apoptotic proteins is a hallmark of cancer. Venetoclax (ABT-199/GDC-0199) is a potent, selective small molecule BCL-2 inhibitor that has shown preclinical and clinical activity across hematologic malignancies and is approved for the treatment of chronic lymphocytic leukemia with 17p deletion as monotherapy and in combination with rituximab. Objective: To investigate the effects of BCL-2 inhibition by venetoclax on viability and function of immune-cell subsets to inform combinability with cancer immunotherapies, such as anti-PD-L1. Methods and Results: B cells, natural killer (NK) cells, CD4+ T cells, and CD8+ T cells in peripheral blood mononuclear cells (PBMCs) from healthy donors (n=3) were exposed to increasing concentrations of venetoclax that are clinically achievable in patients, and percentage of live cells was assessed by flow-cytometry using Near-IR cell staining. B cells were more sensitive to venetoclax (IC50 of ~1nM) than CD8+ T cells (IC50 ~100nM), NK cells (IC50 ~200nM), and CD4+ T cells (IC50 ~500nM) (Figure A). CD8+ T-cell subset analysis showed that unstimulated naive, but not memory cells, were sensitive to venetoclax treatment (IC50 ~30nM and 240nM, respectively). Resistance to venetoclax frequently involves compensation by other BCL-2 family proteins (BCL-XL and MCL-1). As assessed by western blot in PBMCs isolated from healthy donors (n=6), BCL-XL expression was higher in NK cells (~8-fold) and CD4+ and CD8+ T cells (~2.5-fold) than in B cells (1X). MCL-1 protein expression was higher only in CD4+ T cells (1.8-fold) relative to B cells. To evaluate the effect of venetoclax on T-cell function, CD8+ T cells were stimulated ex vivo with CD3/CD28 beads, and cytokine production and proliferation were assessed. Venetoclax treatment with 400nM drug had minimal impact on cytokine production, including interferon gamma (IFNg), tumor necrosis factor alpha (TNFa), and IL-2, in CD8+ effector, effector memory, central memory, and naïve subsets (Figure B). CD8+ T-cell proliferation was similarly resistant to venetoclax, as subsets demonstrated an IC50 >1000nM for venetoclax. Taken together, these data suggest that survival of resting NK and T cells in not impaired by venetoclax, possibly due to increased levels of BCL-XL and MCL-1, and that T-cell activation is largely independent of BCL-2 inhibition. To evaluate dual BCL-2 inhibition and PD-L1 blockade, the syngeneic A20 murine lymphoma model that is responsive to anti-PD-L1 treatment was used. Immune-competent mice bearing A20 subcutaneous tumors were treated with clinically relevant doses of venetoclax, murine specific anti-PD-L1, or both agents. Single-agent anti-PD-L1 therapy resulted in robust tumor regression, while single-agent venetoclax had no effect. The combination of venetoclax and anti-PD-L1 resulted in efficacy comparable with single-agent anti-PD-L1 (Figure C), suggesting that BCL-2 inhibition does not impact immune-cell responses to checkpoint inhibition in vivo. These data support that venetoclax does not antagonize immune-cell function and can be combined with immunotherapy targets. Conclusions: Our data demonstrate that significant venetoclax-induced cell death at clinically relevant drug concentrations is limited to the B-cell subset and that BCL-2 inhibition is not detrimental to survival or activation of NK- or T-cell subsets. Importantly, preclinical mouse models confirm the combinability of BCL-2 and PD-L1 inhibitors. These data support the combined use of venetoclax and cancer immunotherapy agents in the treatment of patients with hematologic and solid tumor malignancies. Figure Figure. Disclosures Lasater: Genentech Inc: Employment. Do:Genentech Inc: Employment. Burton:Genentech Inc: Employment. Li:Genentech Inc: Employment. Oeh:Genentech Inc: Employment. Molinero:Genentech Inc: Employment, Equity Ownership, Patents & Royalties: Genentech Inc. Penuel:Genentech Inc: Employment. Sampath:Genentech Inc: Employment. Dail:Genentech: Employment, Equity Ownership. Belvin:CytomX Therapeutics: Equity Ownership. Sumiyoshi:Genentech Inc: Employment, Equity Ownership. Punnoose:Roche: Equity Ownership; Genentech Inc: Employment. Venstrom:Genentech Inc: Employment. Raval:Genentech Inc: Consultancy, Employment, Equity Ownership.

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A2bR-dependent signaling alters immune cell composition and enhances IL-6 formation in the ischemic heart

AJP Heart and Circulatory Physiology ◽

10.1152/ajpheart.00029.2019 ◽

2019 ◽

Vol 317 (1) ◽

pp. H190-H200 ◽

Cited By ~ 1

Author(s):

Christina Alter ◽

Zhaoping Ding ◽

Ulrich Flögel ◽

Jürgen Scheller ◽

Jürgen Schrader

Keyword(s):

T Cells ◽

B Cells ◽

Regulatory T Cells ◽

Nk Cells ◽

Immune Cells ◽

Cardiac Remodeling ◽

Immune Cell ◽

Ischemic Heart ◽

Cell Composition ◽

Immune Cell Subsets

Although the cardioprotective effect of adenosine is undisputed, the role of the adenosine A2breceptor (A2bR) in ischemic cardiac remodeling is not defined. In this study we aimed to unravel the role A2bR plays in modulating the immune response and the healing mechanisms after myocardial infarction. Genetic and pharmacological (PSB603) inactivation of A2bR as well as activation of A2bR with BAY60-6583 does not alter cardiac remodeling of the infarcted (50-min left anterior descending artery occlusion/reperfusion) murine heart. Flow cytometry of immune cell subsets identified a significant increase in B cells, NK cells, CD8 and CD4 T cells, as well as FoxP3-expressing regulatory T cells in the injured heart in A2bR-deficient mice. Analysis of T-cell function revealed that expression and secretion of interleukin (IL)-2, interferon (IFN)γ, and tumor necrosis factor (TNF)α by T cells is under A2bR control. In addition, we found substantial cellular heterogeneity in the response of immune cells and cardiomyocytes to A2bR deficiency: while in the absence of A2bR, expression of IL-6 was greatly reduced in cardiomyocytes and immune cells except T cells, and expression of IL-1β was strongly reduced in cardiomyocytes, granulocytes, and B cells as determined by quantitative PCR. Our findings indicate that A2bR signaling in the ischemic heart triggers substantial changes in cardiac immune cell composition of the lymphoid lineage and induces a profound cell type-specific downregulation of IL-6 and IL-1β. This suggests the presence of a targetable adenosine–A2bR–IL-6-axis triggered by adenosine formed by the ischemic heart.NEW & NOTEWORTHY Genetic deletion and pharmacological inactivation/activation of A2bR does not alter cardiac remodeling after MI but is associated by compensatory upregulation of various pro- and anti-inflammatory immune cell subsets (B cells, NK cells, CD8 and CD4 T cells, regulatory T cells). In the inflamed heart, A2bR modulates the expression of IL-2, IFNγ, TNFα in T cells and of IL-6 in cardiomyocytes, monocytes, granulocytes and B cells. This suggests an important adenosine–IL-6 axis, which is controlled by A2bR via local adenosine.

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Characterization of the Immune Impact of Daratumumab By Mass Cytometry in Multiple Myeloma

Blood ◽

10.1182/blood-2018-99-119241 ◽

2018 ◽

Vol 132 (Supplement 1) ◽

pp. 4466-4466

Author(s):

Sarah K Johnson ◽

Stephen Burke ◽

Matthew Henry ◽

Amy Greenway ◽

Katie Stone ◽

...

Keyword(s):

Multiple Myeloma ◽

T Cells ◽

B Cells ◽

Nk Cells ◽

Cd8 T Cells ◽

Cell Types ◽

Significant Loss ◽

Regulatory Cells ◽

Mass Cytometry ◽

Lineage Markers

Abstract Background With the advent of antibodies targeted against CD38 the ability to determine which patients will respond and the mechanism by which such response is mediated is imperative for therapeutic success. Immune alterations in multiple myeloma (MM) are known to involve multiple cell types and, therefore we used mass cytometry to study a diverse set of single cells simultaneously. In this work we have studied the immune sequelae of anti-CD38 antibody therapies in a set of multiple myeloma patients. Methods A series of 12 cases of MM were treated with daratumumab (DARA) in a number of disease settings including post-transplant; all had low tumor burden (bone marrow MM plasma cell range 0.001-9.09%). Of the 12 cases assessed, 2 had a partial response (PR) and 3 were deceased within 1 year after start of DARA treatment. Cryopreserved peripheral blood mononuclear cells (PBMC) from 6 healthy donors and 12 myeloma patients were analyzed pre-DARA and at days 28 and 56 after start of therapy. A mass cytometry panel comprising 35 cell surface and 3 intracellular antibodies including cell lineage markers and functional markers was developed. Cells were stained with cell surface antibodies, washed and stained with cisplatin for live-dead discrimination, fixed and permeabilized with FOXP3 staining buffers, and stained with intracellular antibodies. Cells were fixed in PFA containing Iridium intercalator for cell identification, washed and resuspended in ddH2O containing 10% EQ beads and acquired on a Helios mass cytometer. Data were normalized using beads and were transformed using the inverse hyperbolic sine function with a cofactor of 5 and gated for live, intact, singlets for global analysis by manual gating (FCS Express 6) and clustering by viSNE for visualization. Differences in population abundance were identified in an unbiased manner by CITRUS using 13 lineage markers for clustering. Analysis was performed using the multiple testing permutation procedure (SAM), with an FDR of 1% and minimum population size of 1%. Results Manual gating of immune populations revealed that myeloma cases had significant immune perturbations compared to healthy donor PBMCs including loss of CD8+ effector memory, CD4+ T cells, and B cells. Comparison of pre-treatment MM PBMCs to post-DARA therapy showed a significant loss of activated NK cells, B regulatory cells, plasmacytoid dendritic cells, and plasma cells. Interestingly, a significant loss of T regulatory cells (CD4+CD25hiCD127loFOXP3+) was not observed in this analysis. CITRUS identified a total of 26 significant clusters that differentiated the 3 timepoints. Based on the evaluation of phenotypic markers within the clusters, CITRUS identified 4 major cell types that were changed including CD8+ T cells (2 groups, 1 up 1 down post-DARA), NK cells (2 groups, reduced post-DARA), myeloid/monocytes (4 groups, 2 up, 2 down post-DARA) and B cells (reduced post-DARA). CD8+ T cells reduced post-DARA were distinguished by the presence of CD38, elevated CD57 and lack of HLA-DR compared to CD8 T cells that increased at D28 but returned to baseline levels by D56. The two NK cell groups were differentiated by the presence of CD16, representing activated cells. The 4 myeloid groups altered were characterized by the phenotype (CD14+CD11b+CD11c+CD33+), and the addition of CD38 in the two groups reduced post-DARA, which may represent myeloid derived suppressor cells and myeloid dendritic cells. Another CITRUS analysis was performed with identical settings to examine changes in median expression of markers. Two groups of 5 clusters were identified based on CD55 or CD59 intensity, markers associated with complement inhibition. The CD55 group (4 clusters, CD56+CD16+) was upregulated at days 28 and 56 compared to pre-DARA. The CD59 group (1 cluster, CD38hiCD45lo) was reduced overall at day 28 and 56, however the cases were bimodal in terms of the extent of reduction. As this population most likely represents myeloma PCs, CD59 may be a surrogate for the presence of circulating tumor cells. Conclusions Significant changes in immune status post-DARA were identified by the comprehensive analysis of immune population abundance and marker intensity using mass cytometry. Significant changes in CD8+ T cells, NK cells, B cells, monocytes and in CD55 and CD59 intensity were observed post-DARA. Disclosures Morgan: Takeda: Consultancy, Honoraria; Celgene: Consultancy, Honoraria, Research Funding; Janssen: Research Funding; Bristol-Myers Squibb: Consultancy, Honoraria.

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The immune cell landscape of peripheral blood mononuclear cells from PNS patients

Scientific Reports ◽

10.1038/s41598-021-92573-6 ◽

2021 ◽

Vol 11 (1) ◽

Author(s):

Qing Ye ◽

Chao Zhou ◽

Sisi Li ◽

Jingjing Wang ◽

Fei Liu ◽

...

Keyword(s):

T Cells ◽

Nephrotic Syndrome ◽

B Cells ◽

Nk Cells ◽

Cd8 T Cells ◽

Immune Cells ◽

Peripheral Blood ◽

Mononuclear Cells ◽

Immune Cell ◽

Immunological Mechanism

AbstractExisting research suggests that the human immune system and immune cells are involved in the pathogenesis of nephrotic syndrome, but there is still a lack of direct evidence. This study tried to analyze the profiling of immune cells in the peripheral blood of steroid-sensitive nephrotic syndrome (SSNS) patients and steroid-resistant nephrotic syndrome (SRNS) patients before and after standard steroid treatment to clarify the immunological mechanism of nephrotic syndrome patients. The number and proportion of CD4 + T cells in patients with nephrotic syndrome remained unchanged. However, there is an imbalance of Th1 and Th2 and an excessive increase of Th17 cells. The number of CD8 + T cells and the number of effector CD8 + T cells in them increased significantly, but only in SSNS, the number of activated CD8 + T cells increased, and the number of activated Treg cells decreased significantly. Nephrotic syndrome patients also have B cell disorder, and it is more prominent in SSNS patients. Compared with the normal control, only the number of B cells and plasmablast in SSNS patients increased significantly (Z = − 2.20, P = 0.028). This study also observed that transitional B cells decreased in both SSNS and SRNS patients, but SSNS patients' decrease was lower than in SRNS patients. Compared with normal controls, monocytes in patients with nephrotic syndrome decreased significantly. The main reason was that Non-classical Monocyte decreased, while Classical Monocyte increased slightly. The total number of NK cells did not change, but the internal cell subgroups' composition occurred. Changes, realized as CD56hi NK cells increased, CD56low NK cells decreased; and the above trend is more evident in SSNS patients. Patients with nephrotic syndrome have immune disorders, including T cells, B cells, Monocytes, and NK cells. It can be confirmed that immune factors are involved in the pathogenesis of the nephrotic syndrome.

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Peripheral immune circadian variation, synchronisation and possible dysrhythmia in established type 1 diabetes

Diabetologia ◽

10.1007/s00125-021-05468-6 ◽

2021 ◽

Author(s):

Craig A. Beam ◽

Eleni Beli ◽

Clive H. Wasserfall ◽

Stephanie E. Woerner ◽

Megan T. Legge ◽

...

Keyword(s):

T Cells ◽

Type 1 Diabetes ◽

B Cells ◽

Regulatory T Cells ◽

Cd8 T Cells ◽

Immune Cell ◽

Circadian Variation ◽

Time Of Day ◽

Effector Memory

Abstract Aims/hypothesis The circadian clock influences both diabetes and immunity. Our goal in this study was to characterise more thoroughly the circadian patterns of immune cell populations and cytokines that are particularly relevant to the immune pathology of type 1 diabetes and thus fill in a current gap in our understanding of this disease. Methods Ten individuals with established type 1 diabetes (mean disease duration 11 years, age 18–40 years, six female) participated in a circadian sampling protocol, each providing six blood samples over a 24 h period. Results Daily ranges of population frequencies were sometimes large and possibly clinically significant. Several immune populations, such as dendritic cells, CD4 and CD8 T cells and their effector memory subpopulations, CD4 regulatory T cells, B cells and cytokine IL-6, exhibited statistically significant circadian rhythmicity. In a comparison with historical healthy control individuals, but using shipped samples, we observed that participants with type 1 diabetes had statistically significant phase shifts occurring in the time of peak occurrence of B cells (+4.8 h), CD4 and CD8 T cells (~ +5 h) and their naive and effector memory subsets (~ +3.3 to +4.5 h), and regulatory T cells (+4.1 h). An independent streptozotocin murine experiment confirmed the phase shifting of CD8 T cells and suggests that circadian dysrhythmia in type 1 diabetes might be an effect and not a cause of the disease. Conclusions/interpretation Future efforts investigating this newly described aspect of type 1 diabetes in human participants are warranted. Peripheral immune populations should be measured near the same time of day in order to reduce circadian-related variation. Graphical abstract

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Engineered immunostimulatory cells can convert PBMCs from chronic lymphocytic leukemia (CLL) patients into potent tumor killing immune cells.

Journal of Clinical Oncology ◽

10.1200/jco.2021.39.15_suppl.7517 ◽

2021 ◽

Vol 39 (15_suppl) ◽

pp. 7517-7517

Author(s):

Joshua W. Keegan ◽

Frank Borriello ◽

Stacey M. Fernandes ◽

Jennifer R. Brown ◽

James A. Lederer

Keyword(s):

T Cells ◽

B Cells ◽

Tumor Cell ◽

Nk Cells ◽

Cd8 T Cells ◽

Immune Cells ◽

Killing Activity ◽

Tumor Killing ◽

Tumor Cell Killing ◽

Potent Tumor

7517 Background: Alloplex Biotherapeutics has developed a cellular therapeutic that uses ENgineered Leukocyte ImmunoSTimulatory cell lines called ENLIST cells to activate and expand populations of tumor killing effector cells from human peripheral blood mononuclear cells (PBMCs). This process leads to a 300-fold expansion of NK cells, CD8+ T cells, NKT cells, and TCRγδ T cells that are called SUPLEXA cells, which will be cryopreserved and transferred back into patients as an autologous immune cell therapy for cancer. In this study, PBMCs from CLL patients were used to generate SUPLEXA cells as a first approach to comparatively profile SUPLEXA cells from cancer patients and normal healthy volunteers (NHVs). Methods: ENLIST cell lines were engineered by expressing curated immunomodulatory proteins in the SK-MEL-2 melanoma cell line. Two million (M) PBMCs from 10 CLL patients or 2 NHVs were incubated with 0.4 M freeze/thaw killed ENLIST cells for 5 days in XVIVO-15 medium with 2% heat-inactivated human AB serum (XAB2) and then split 1:15 in XAB2 containing IL-7 and IL-15 to expand. After 9 days, SUPLEXA cells were harvested and cryopreserved. Results: Original PBMCs and matched SUPLEXA cells from each donor were thawed and characterized by mass cytometry (CyTOF) using a 47-marker antibody panel. CyTOF staining results of PBMCs from CLL patients demonstrated approximately 95% leukemia cells and few T cells, NK cells, B cells, and monocytes. CyTOF staining of SUPLEXA cells from all 10 CLL patients showed expansion of NK cells (17%), CD8 T cells (11%), and CD4 T cells (7.5%) that were similar in phenotype to SUPLEXA cells from NHVs showing high expression of granzymes and perforin that are indicative of potent tumor cell killing activity. Cancer cells in the original CLL PBMC samples were reduced to 0.78%. However, a population of non-T/non-B cells (60% ± 9.5%) was detected in SUPLEXA cells from all CLL patients that require further characterization. Next, SUPLEXA cells from CLL and NHV patients were comparatively tested for tumor cell killing activity at 2:1, 1:1, and 1:2 effector to target cell (MEL-14 melanoma cells expressing RFP) ratios. Percent killing of tumor cells by SUPLEXA cells prepared from CLL patients (77.8% ± 2.6% at 2:1) and NHVs (81.5% ± 0.3% at 2:1) were nearly identical at all effector to target ratios. Conclusions: We demonstrate for the first time that PBMCs from CLL patients can be converted into SUPLEXA cells despite low numbers of normal immune cells at baseline and the known immunologic impairment present in CLL patients. Importantly, SUPLEXA cells derived from CLL patients acquire potent tumor killing activity that is indistinguishable from SUPLEXA cells prepared from NHVs. Taken together, these findings support the feasibility of converting PBMCs from CLL patients with low percentages of NK and T cells into an autologous cellular therapy for cancer.

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Short-Term Immunopathological Changes Associated with Pulse Steroids/IVIG/Rituximab Therapy in Late Kidney Allograft Antibody Mediated Rejection

Kidney360 ◽

10.34067/kid.0001082019 ◽

2020 ◽

Vol 1 (5) ◽

pp. 389-398

Author(s):

Kenna R. Degner ◽

Nancy A. Wilson ◽

Shannon R. Reese ◽

Sandesh Parajuli ◽

Fahad Aziz ◽

...

Keyword(s):

T Cells ◽

B Cells ◽

Regulatory T Cells ◽

B Cell ◽

Cd8 T Cells ◽

Hla Class I ◽

B Cell Depletion ◽

Short Term ◽

Antibody Mediated Rejection ◽

Pulse Steroids

BackgroundB cell depletion is a common treatment of antibody-mediated rejection (ABMR). We sought to determine the specific immunopathologic effects of this therapeutic approach in kidney transplantation.MethodsThis was a prospective observational study of recipients of kidney transplants diagnosed with late ABMR (>3 months after transplant). Patients received treatment with pulse steroids, IVIG, and rituximab. Donor-specific HLA antibodies (DSA), kidney allograft pathology, renal function, immune cell phenotypes, and 47 circulating cytokines were assessed at baseline and at 3 months.ResultsWe enrolled 23 patients in this study between April 2015 and March 2019. The majority of patients were male (74%) and white (78%) with an average age of 45.6±13.8 years. ABMR was diagnosed at 6.8±5.9 years (4 months to 25 years) post-transplant. Treatment was associated with a significant decline in circulating HLA class I (P=0.003) and class II DSA (P=0.002) and peritubular capillaritis (ptc; P=0.04) compared to baseline. Serum creatinine, BUN, eGFR, and proteinuria (UPC) remained stable. Circulating B cells were depleted to barely detectable levels (P≤0.001), whereas BAFF (P=0.0001), APRIL (P<0.001), and IL-10 (P=0.02) levels increased significantly post-treatment. Notably, there was a significant rise in circulating CD4+ (P=0.02) and CD8+ T cells (P=0.003). We also noted a significant correlation between circulating cytotoxic CD8+ T cells and BAFF (P=0.05), regulatory T cells and IL-10 (P=0.002), and regulatory T cells and HLA class I DSA (P=0.005).ConclusionsShort-term pulse steroids/IVIG/rituximab therapy was associated with inhibition of ABMR (DSA and ptc), stabilization of kidney function, and increased regulatory B cell and T cell survival cytokines. Additional studies are needed to understand the implications of B cell depletion on the crosstalk between T cells and B cells, and humoral components that regulate ABMR.

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GDF15 expression in metastatic colorectal cancer.

Journal of Clinical Oncology ◽

10.1200/jco.2021.39.3_suppl.116 ◽

2021 ◽

Vol 39 (3_suppl) ◽

pp. 116-116

Author(s):

Priya Jayachandran ◽

Joanne Xiu ◽

Shivani Soni ◽

Richard M. Goldberg ◽

Benjamin Adam Weinberg ◽

...

Keyword(s):

Colon Cancer ◽

T Cells ◽

Nk Cells ◽

Chromatin Remodeling ◽

Cancer Progression ◽

Cd8 T Cells ◽

Immune Cell ◽

Checkpoint Inhibitors ◽

Metastatic Colon Cancer ◽

Genomic Alterations

116 Background: Cachexia affects many cancer patients. Growth differentiation factor-15 (GDF15) is a protein that regulates weight and the stress response of cells. The GDF15 gene encodes a ligand of TGF-beta that triggers cachexia and modulates the progression from tumorigenesis to metastasis. Inhibition of GDF15 with an antibody restored muscle mass and fat in animal models. Serum levels rise in proportion to the progression of colon cancer, predict outcome, and have been correlated with CEA. Methods: We retrospectively reviewed 7607 CRC tumors profiled by Caris Life Sciences (Phoenix, AZ) from 2019 to 2020. Profiling included whole transcriptome sequencing (RNA-Seq by NovoSeq). Tumor mutational burden, mismatch repair status, and pathway genomic alterations were evaluated. QuantiSEQ was used to assess immune cell infiltration in the tumor microenvironment. Results: GDF15 expression ranged from 0 to 593 transcripts per million (TPM) with median of 30 (IQR = 15.02). There was no association with age, sex, or primary tumor sidedness. MSI-H/dMMR tumors had higher GDF15 expression (median 37 vs 30, p = 0.0004); TMB > = 17 tumors was seen in 5.9% of bottom quartile (Q1) GDF15 expressors and 8.3% of top quartile (Q4). PDL1 IHC positivity was inversely correlated with GDF15 expression (7.1% in Q1 vs. 2.6% in Q4, p < 0.0001). Genomic alterations associated with higher GDF15 expression (Q4 vs Q1) included genes on TGF-B (SMAD2/4), PI3K (PIK3CA, MTOR), chromatin remodeling (ARID1A, KMT2C), DDR (ATM) and Wnt pathway (APC); those inversely associated included MYC CNA and TP53. Q1 tumors had higher CNA of ERBB2 and FGFR1. Relative neutrophils and NK cells in the TME increased from Q1 to Q4 (p < 0.001). There was a decrease in CD8+ T-cells and Treg cells from Q1 to Q4. Conclusions: GDF15 expression correlates with increased dMMR/MSI-H and TMB, but not with PDL1 expression. Mutations and activated pathways associated with GDF15 expression may explain increased cachexia with more aggressive disease. The association with chromatin remodeling may warrant therapies targeting histone modification and epigenetics. The increase in NK cells but decrease in CD8+ T cells in the TME with increasing GDF15 suggests approaches to treatment. Higher CD8+ lymphocyte counts correlate with PFS with immunotherapy. Anti-PD-L1 therapy reinvigorates the killing function of CD8+ T cells. The decrease in CD8+ T cells and PDL1 positivity with rising GDF15 suggests worse outcome and a lack of response to anti-PDL1 therapy. NK cell checkpoint inhibitors, CARs, and an anti-GFRAL antibody are now in clinical trials and might be utilized in high GDF15 cancers. GDF15 is emerging as a target in the treatment of obesity and cachexia and as a prognostic marker in oncology. Understanding its expression in metastatic colon cancer may reveal which patients could benefit from developing anti-GDF15 targeted therapies against cancer progression.

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B and NK Cells Closely Correlate with the Condition of Patients with Acute Pancreatitis

Gastroenterology Research and Practice ◽

10.1155/2019/7568410 ◽

2019 ◽

Vol 2019 ◽

pp. 1-13 ◽

Cited By ~ 1

Author(s):

Xin Wei ◽

Weifeng Yao ◽

Huiping Li ◽

Jingjing Qian ◽

Yaosheng Xie ◽

...

Keyword(s):

Acute Pancreatitis ◽

B Cells ◽

Hospital Stay ◽

B Cell ◽

Nk Cells ◽

Length Of Hospital Stay ◽

Absolute Number ◽

Frequency Change ◽

Short Term Treatment ◽

Cell Frequency

Purpose. Pancreatitis can lead to systemic inflammatory response, but the relationship between lymphocyte changes and patients with pancreatitis remains unclear. In this study, we evaluated the feedback function of changes in peripheral lymphocyte subsets on the condition of patients with pancreatitis. Materials and Methods. 131 acute pancreatitis (AP) patients and 11 chronic pancreatitis (CP) patients constituted the patients’ group; 20 healthy individuals were enrolled as healthy controls (HC). Serum concentration of C-reactive protein (CRP), amylase, and lipase and the frequency and absolute number of many types of peripheral lymphocytes (including T, B, NK, CD16+/CD56+ T, CD4+ T, CD8+ T, CD4+CD8+ T, and CD4−CD8− T cells) were detected on admission and the seventh day of standard treatment. Besides, the length of hospital stay was recorded. Results. The absolute number of all lymphocytes we studied decreased in patients with CP and in patients with almost all types of AP. The frequency change of lymphocytes varies among the different types of AP. During disease onset, B cell frequency correlated positively with CRP concentration and NK cell frequency correlated positively with amylase and lipase concentration. B cell frequency and CD4+ T cell absolute number were recovering towards normal after short-term treatment. The frequency of B cells and NK cells correlated positively with the length of hospital stay. Conclusions. B cells and NK cells closely correlate with patients’ condition and may help to diagnose AP more accurately and reflect treatment effect of AP in time, affecting the recovery speed of patients with M-AP, which may help physicians to better understand the pathophysiology of pancreatitis.

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