bluuebunny/crossref_metadata_2025_split huggingface dataset:
Induction of immune tolerance by CGEN-15001, a novel immunomodulatory Fc fusion protein of the B7 family (THER5P.823)
Authors: Hecht Iris , Vaknin Ilan , Oren Anat , Toporik Amir , Tarcic Nora , Rotman Galit , Neria Eyal , Keren Aviad , Gilhar Amos , McNamee Kay , Williams Richard , Miller Stephen , Podojil Joseph 
Published: January 2023

Abstract
We discovered a novel immune checkpoint protein based on characteristics of the B7/CD28 family. CGEN-15001 is a fusion protein composed of the extracellular domain of this protein fused to IgG Fc. CGEN-15001 inhibits T cell activation, demonstrates immunomodulation by inhibiting pro-inflammatory Th1 and Th17 responses while promoting anti-inflammatory IL-10 and Th2 responses, and enhances iTreg differentiation. CGEN-15001 is efficacious in animal models of autoimmunity such as multiple sclerosis (MS), rheumatoid arthritis, type1 diabetes (T1D) and psoriasis. In the EAE model of MS and in the NOD model of T1D, short 2-week treatment with CGEN-15001 resulted in long term inhibition of disease. In the T1D model, mice treated with CGEN-15001 retained normal blood glucose levels18 weeks after cessation of treatment. To further study tolerance induction, the H-Y minor Ag mismatch bone marrow transplantation model was used. CGEN-15001 treatment resulted in graft survival and increase in Tregs, indicating donor specific tolerance induction. The prolonged therapeutic responses in models of autoimmunity and the prevention of graft rejection, imply establishment of immune tolerance by CGEN-15001. Taken together, the mode of action of CGEN-15001 that combines inhibition of autoreactive cells, immunomodulation and restoration of immune tolerance, suggests it should provide long standing and safe therapy for autoimmune diseases.
Deletional therapy for harmful immune responses: beyond chemotherapy (THER5P.828)
Authors: Jordan Michael , Hildeman David , Katz Jonathan , Millen Scott 
Published: January 2023

Abstract
Immune suppressive therapies may be categorized as either inhibitory (e.g. inhibitors of co-stimulatory pathways, intracellular signaling pathways, various cytokines, etc.) or deletional (e.g. anti-T or B cell antibodies, chemotherapy to kill activated lymphocytes, etc.). While inhibitory therapies may be tailored to a specific application, they are never truly immune selective because any immune pathway may be involved in both pathologic and protective immune responses. Similarly, depletional strategies may have non-specific effects on the immune system and significant off target toxicities (e.g. genotoxicity). We have recently reported the exquisite immune selectivity of etoposide, though this agent still has non-immune toxicities related to its non-specific DNA damaging mechanism. We have now found that the replicative stress experienced by recently activated T cells leads to a strong spontaneous DNA damage response (DDR), sensitizing them to DNA-damaging agents. Thus, we hypothesized that non-DNA damaging agents designed to therapeutically exploit the DDR would impair the ability of T cells to cope with intrinsic genotoxic stresses and would have therapeutic potential. We have now found a series of novel agents which impair cell cycle checkpoints and/or potentiate pro-apoptotic effects of the DDR which potently delete activated T cells in vivo while sparing resting naïve and memory T cells, thus implicating novel, antigen-specific forms of immune suppressive therapy.
High efficacy of Toll-like receptor 4 targeting in murine and humanized models of rheumatoid arthritis in comparison with IL-1 and TNF inhibitors (THER6P.860)
Authors: Abdollahi Shahla , Koenders Marije , Joosten Leo , van de Loo Fons , van den Berg Wim 
Published: January 2023

Abstract
Enhanced expression of Toll-like Receptor (TLR) 4 and its endogenous agonists in rheumatoid joints suggests involvement in rheumatoid arthritis (RA). We assessed therapeutic efficacy and downstream effects of TLR4 blockade in murine and humanized models of RA compared with interleukin-1 (IL-1) and tumor necrosis factor (TNF) inhibitors. TLR4 blockade using purified B. quintana LPS suppressed established collagen-induced arthritis, and reduced serum IL-1β and IL-6 concentrations to the same extent as IL-1 and TNF inhibitors. TLR4 targeting exceeded beneficial effects of TNF blocker by reducing serum TNFα and IL-17 along with synovial expression of IL-23p19, IL-17 and the Th17-related transcription factor RORγt, while Th1 markers and type II collagen-directed T cell proliferation and antibody responses remained unaffected. To translate the findings into human disease, RA synovial biopsies were engrafted into SCID mice. TLR4 inhibition in this model resulted in reduction of spontaneous IL-6 and IL-8 release by RA synovium and reduced synovial inflammation, thereby equaling anti-TNF therapy. In ex vivo cultures of RA synovial explants, high-density protein microarray revealed suppressed activation of multiple key signaling molecules including NFκBp65 phospho-Ser536 (27%), TAK1 phospho-Thr187 and -Ser412 (26 and 23%, resp.), JAK1 phospho-Tyr1022 (22%), IRF3 (51%), Foxo3a (39%) and Btk (24%). The data collectively suggest TLR4 as a potential therapeutic target in RA.
B cells are required for CD8 T cell recovery after antibody-mediated depletion (TRAN3P.895)
Authors: Ayasoufi Kathy , Wang Xi , Valujskikh Anna 
Published: January 2023

Abstract
Antibody-mediated lymphoablation is used as an induction therapy in transplant patients. We investigated the requirements for T cell recovery following lymphoablation in a mouse model of heart transplantation. Memory CD4 T cells are less susceptible to depletion by murine antithymocyte globulin (mATG) than CD8 T cells. Additional CD4 T cell depletion impaired CD8 T cell recovery after mATG treatment in B6 recipients of BALB/c heart allografts and in non-transplanted B6 mice. Treatment with blocking anti-CD154 mAb plus mATG inhibited CD8 T cell recovery, while agonistic anti-CD40 mAb restored memory CD8 T cell expansion after mATG treatment of CD4 T cell depleted recipients. To test whether B cells are required for CD8 T cell recovery, we used B6.huCD20tg mice. Treatment with anti-human CD20 mAb depleted &gt;90% of peripheral B cells and markedly inhibited CD8 T cell expansion in huCD20tg recipients compared to B cell-sufficient mice. Next, B cells were isolated from mATG treated recipients with or without CD4 depletion. In the absence of CD4 T cells, B cells expressed lower levels of MHC class I, CD80, CD86, and TNFα suggesting that both cognate interactions and cytokines promote CD8 T cell expansion. Our results show that CD4 T cell help mediated through B cells and CD40/CD154 interactions drives CD8 T cell reconstitution following antibody-mediated depletion. These findings may be used to improve the efficiency of lymphoablation in sensitized transplant recipients.
Comparative immunological study of of lamellar and penetrating keratoplasty in murine model (TRAN3P.906)
Authors: Lee Hyun Soo , Choi Min-Young , Joo Choun-Ki 
Published: January 2023

Abstract
Lamellar keratoplasty (LK) has been considered an acceptable alternative surgery for penetrating keratoplasty (PKP), because LK has the advantage of lower risk of graft rejection and intraocular complications, according to recent clinical outcomes. But the relative immunological mechanism of graft rejections for the two procedures is uncertain. We have developed a murine model of lamellar keratoplasty to try to understand the immunological mechanisms of those two procedures. Our results demonstrate that LK mice showed less graft rejection than PK mice and LK led to less DTH response and IFN-γ secretion in vitro recall assay of T cells from drainage cervical lymph nodes (LNs) at day 21, as compared to PK (acceptance; acc). There was no difference of mRNA expressions of IL-1β, IL-6, and IFN-γ in the corneas between two groups at day 5, but mRNA expressions of IL-1β and IFN-γ in PKacc mice were significantly increased at day 28. In addition, LK showed less angiogenesis and lymphangiogenesis in grafted cornea than PK, and LK led to decreased number of mature MHC-IIhighCD11c+ antigen presenting cells (APCs) in the draining LNs of transplanted mice, compared with PKacc. In conclusion, these results show that LK presents less graft rejection than PK through lower angiogenesis and lymphangiogenesis, which could make pathologic T cells and APC less migration into drainage LNs and grafted corneas, respectively.
Inhibition of indoleamine 2,3-dioxygenase enhances graft-versus-leukemia effect after donor leukocyte infusion in mice: differential efficacy of 1-methyl tryptophan isomers (TRAN3P.907)
Authors: Lim Ji young , Park Gyenogsin , Choi Eun Young , Min Chang-Ki 
Published: January 2023

Abstract
Indoleamine 2,3-dioxygenase (IDO) is the first and rate-limiting enzyme of tryptophan catabolism through kynurenine (KYN) pathway, has an important role in immunomodulation. Moreover, it was shown that treating mice with 1-methyl tryptophan (1-MT), a small-molecule inhibitor of IDO, could break the tolerogenic state, providing antitumor responses. Despite the role of IDO in the induction of tumor immune tolerance, the direct role of IDO inhibition on GVL and GVHD still remains obscure. We established a murine GVL model. Recipient mice were sublethally irradiated and were transplanted with donor bone marrow cells on day 0. Recipient mice were receiving with or without DLI on day 14. Two isomers of IDO inhibition (D-1MT and L-1MT, 100mg/kg) were administered for 5 days per week from the day of P815 cell inoculation until 4 weeks. Both 1-MT isomers administration reduced leukemia growth in mice with CC. On the other hand, L-1MT but not D-1MT reduced leukemia growth in mice with MC. IDO expressions was increased in TDLN and tumor tissues of the CC mice but not in the MC mice. Accordingly plasma concentrations of KYN were increased in the CC mice on day 14 and treatment of both 1-MT isomers abrogated its production. These results demonstrate both isomers of 1-MT enhanced DLI-induced GVL after transplantation, possibly mediated by inhibition of IDO activity in the tumor microenvironment. L-1MT but not D-1MT may directly abrogate leukemia growth regardless of the expressions of IDO.
Islet allograft destruction in NOD mice is independent of donor MHC expression (TRAN3P.870)
Authors: Burrack Adam , Beilke Joshua , Kupfer Tinalyn , Beard K. Scott , Coulombe Marilyne , Gill Ronald 
Published: January 2023

Abstract
It is unclear whether autoimmune disease recurrence overlaps with allograft immunity in the autoimmune diabetic recipient of a pancreatic islet transplant. We grafted autoimmune NOD mice with either syngeneic NOD or allogeneic C57Bl/6 (B6) islets that were genetically deficient in MHC class I, MHC class II, or both MHC class I and MHC class II. NOD.RAG-/- or MHC II-deficient NOD islets were acutely destroyed, but depletion of CD8+ T cells significantly prolonged graft survival. Most NOD MHC I-deficient or MHC I/II-deficient islets survived long-term (&gt;100 d). In contrast, B6 allografts that were MHC sufficient, or deficient in MHC class I, class II, or both were acutely rejected. Allograft rejection was CD4+ T cell dependent and CD8+ T cell independent. Of note, islet allograft rejection in non-autoimmune recipients requires donor islet MHC I or MHC II expression. Lastly, autoimmune disease recurrence was accelerated by depletion of CD25+ cells. We hypothesize that autoimmune disease recurrence is primarily a CD8+ T cell mediated response restricted by donor MHC class I molecules and is delayed by CD4+CD25+ regulatory T cells. In contrast, results suggest that CD4+ T cells play a predominant role in allograft rejection in the autoimmune recipient. We propose the lack of down-regulation of the anti-allograft response and the presence of primed autoreactive T cells synergize to produce the rapid allograft rejection observed in the autoimmune islet transplant recipient.
Oral rapamycin (eRapa) safely prevents carcinogen-induced dermal carcinogenesis through an interferon-γ-dependent mechanism (TUM7P.931)
Authors: Dao Vinh , Hurez Vincent , Pandeswara Sri Lakshmi , Cardenas Kim , Sun Lishi , Liu Aijie , Hasty Paul , Sharp Z. Dave , Curiel Tyler 
Published: January 2023

Abstract
eRapa extends life in mice and cancer prevention could be a mechanism. Rapamycin inhibits mTOR, which has significant immune effects that are surprisingly unstudied in cancer therapy or prevention. We hypothesize that cancer prevention by eRapa is mediated by improved cancer immune surveillance, which we tested in the well-established DMBA/TPA carcinogen-induced skin cancer model. Mice got eRapa or control chow, and skin tumors were induced with DMBA/TPA over 24 weeks. eRapa reduced benign (p=.001) and malignant (p=.05) tumors in WT mice. T cells and IFN-γ mediate cancer immune surveillance. eRapa reduced skin tumors in βδ KO mice lacking all T cells (p=.04), but not in IFN-γ KO mice (p=.13), consistent with loss of beneficial eRapa-induced, non-T cell IFN-γ. In support, WT or IFN-γ KO T cell transfer into IFN-γ KO mice did not alter eRapa cancer prevention in DMBA/TPA. In WT mice on DMBA/TPA, eRapa increased IFN-γ-producing natural killer cells (p=.01) that could mediate skin cancer immune surveillance, and decreased CD34+CD49fint skin cancer stem cells (p=.01) and CXCR3+ T cells (p&lt;.001) that contribute to cancer in this model. eRapa reduced skin pAKT with divergent mTORC1/2 effects needing more study. eRapa appeared safe (no increased Tregs or reduced protection in infection and autoimmunity models). A widely applicable, safe and tolerable cancer prevention agent would be highly useful. Understanding its immune mechanisms could improve efficacy and widen applications.
Characterization of a novel anti-CD20 StradobodyTM with potent in vitro anti-tumor activity (TUM7P.935)
Authors: Zhang Xiaoyu , Burch Erin , Chen Shaodong , Sallin Michelle , Olsen Henrik , Block David , Strome Scott 
Published: January 2023

Abstract
Despite the efficacy of anti-CD20 mAb in the treatment of B-cell malignancies, a proportion of patients are non-responsive or relapse after mAb therapy. Therefore, developing more effective mAbs represents a major area of interest. In this study, we assessed a novel anti-CD20 antibody (stradobodyTM from Gliknik Inc.) consisting of an unmodified Fab sequence and a multimerized Fc domain. In vitro, the anti-CD20 stradobodyTM mediates significantly enhanced inhibition of cell proliferation on select B lymphoma cell lines relative to the unmodified anti-CD20 mAb. In addition, B lymphoma cell lines exhibit increased susceptibility to Complement Dependent cytotoxicity in the presence of a low concentration of the anti-CD20 stradobodyTM. However, anti-CD20 stradobodyTM did not elicit enhanced anti-tumor efficacy in vivo in a Raji-scid xenograft model, in comparison with unmodified anti-CD20 mAb. This discrepancy of in vitro and in vivo anti-tumor efficacy of anti-CD20 stradobodyTM might be attributable to less avidity of the modified human Fc domain to the murine receptors compared with human receptors and highlights the challenges with validating novel targeted mAb therapeutics in vivo.
Role of IL-13 and its receptors in the pathogenesis of cutaneous T-cell lymphomas (TUM7P.961)
Authors: Fuschiotti Patrizia , Devlin Jason , Stolz Donna , Viragova Sara , Falo Lou , Geskin Larisa 
Published: January 2023

Abstract
Cutaneous T-cell lymphomas (CTCL) affect primarily skin and are characterized by proliferation of mature CD4+ T-helper cells. Diagnose is difficult in the absence of specific markers for malignant lymphocytes. The pattern of cytokine production in the skin and blood is considered to be of major importance for the pathogenesis of CTCL. Abnormal cytokine expression in CTCL may be responsible for enhanced proliferation of the malignant cells and/or the depression of the anti-tumor immune response. Cytokine IL-13 promotes growth or survival of several tumors as well as suppresses immunosurveillance. Here we show that IL-13 and its receptors IL-13Rα1 and IL-13Rα2 are highly expressed in the clinically involved skin of CTCL patients. We also show that the tumor cells, identified by the expression of CD4 and TOX (thymus high-mobility group box), in the skin and blood of CTCL patients produce IL-13 and express both receptors. This finding is intriguing since CTCL is a T-cell origin tumor yet T cells do not express IL-13 receptors. Thus IL-13 is implicated as a possible autocrine factor for CTCL. Furthermore expression of the decoy IL-13Rα2 by CTCL cells may represent a novel marker of CTCL malignancy. Soluble human IL-13Rα2 and an anti-IL-13 monoclonal antibody are being tested for inhibition of tumor cell proliferation in the peripheral blood of patients. Altogether these results identify potential tumor markers for the early diagnosis of CTCL as well as novel therapeutic targets.
Constitutive signaling through Myd88 contributes to tumor-derived CCL2 expression and nuclear translocation of NFkB p65, p52, Fos and ATF2 (TUM7P.923)
Authors: Kurt Robert , Serrano Antonio , Boateng Kofi , Parsons Victoria , Phuong Tiffany , Ricca Jacob , Tucker Kyle , Eidelman Alec , Carey Maureen 
Published: January 2023

Abstract
Previous data in our lab suggested that there may be constitutive signaling through the Myd88 signaling cascade in murine mammary carcinoma. Here we extend these findings by showing that the myddosome complex is preformed in the tumor cells. Using co-immunoprecipitation we found Myd88 associated with IRAK2 and IRAK4. After screening many different products of the TLR signaling cascade we found that the most clear consequence of this Myd88 signaling in the tumor cells was expression of CCL2. Targeting Myd88 expression using RNA interference, or function using an inhibitory peptide, resulted in reduced CCL2 expression in a dose dependent manner. Coinciding with Myd88 dependent expression of CCL2 we also detected presence of the CCL2 transcriptional factors NFkB p65, p52, Fos and ATF2 in the nucleus of the tumor cells, and the levels of these proteins in the nucleus decreased upon treatment with the Myd88 inhibitory peptide. Targeting Myd88 using the inhibitory peptide, constitutive shRNA expression, or tetracycline inducible shRNA expression also resulted in a reduced tumor growth rate in vitro. Despite this we found limited therapeutic potential of targeting Myd88 in vivo using the inhibitory peptide alone. Collectively, these data imply that constitutive Myd88 signaling contributes to tumor-derived CCL2 expression, and suggests that alternative mechanisms to target Myd88 in vivo warrants investigation.
ATM-deficiency in the absence of T cells promotes the development of B cell lymphomas with dependence on NF-kB (TUM7P.927)
Authors: Hathcock Karen , Padilla-Nash Hesed , Camps Jordi , Triner Daniel , Shin Dong-Mi , Maul Robert , Gearhart Patricia , Morse Herbert , Ried Thomas , Hodes Richard 
Published: January 2023

Abstract
The protein product of the ataxia-telangiectasia mutated gene, ATM, is a kinase that plays a central role in maintaining genomic integrity and protecting cells from oncogenic transformation. Mutations of the human ATM gene cause ataxia-telangiectasia, an autosomal recessive disorder that is associated with increased incidence of malignancies, especially lymphoid tumors. ATM-deficient mice have been useful tools to study thymic lymphomas, which occur at high frequency in these mice, but the early onset of these tumors has prevented analysis of other types of malignancies. In this study we generated ATM- and CD3ε-deficient mice that lacked T cells. These mice do not develop thymic lymphomas, but routinely develop early onset B cell lymphomas that express surface markers characteristic of mature activated B cells. These B cell lymphomas resemble human diffuse large B cell (DLBC) lymphomas and possess complex karyotypes with genetic amplifications, deletions and unbalanced translocations. Interestingly all lymphomas (10/10) contain an amplification of a 5Mb region on chromosome 18 containing MALT1. These lymphomas also express NF-kB and are dependent on MALT1 and NF-kB signaling for in vitro survival. As such they represent a mouse model for NF-kB- dependent human DLBC lymphomas of the ABC- subtype.
Activation of natural killer T cells by liposomal glycosphingolipids increases the efficacy of liposomal doxorubicin against DMBA-induced tumors in mice (VAC10P.968)
Authors: Khan Masood , Aljarbou Ahmad , Aldebasi Yosef 
Published: January 2023

Abstract
Natural Killer T (NKT) cells show potent antitumor activity upon activation with their specific ligands. Glycosphingolipids (GSLs) isolated from Sphingomonas paucimobilis were incorporated into DPPC-liposomes to prepare GSL-incorporated liposomes (GSL-liposomes). Treatment of tumor-bearing mice with a combination of GSL-liposomes and doxorubicin liposomes resulted into slowing down of the progression of tumors and increase in the survival of mice. Splenocytes obtained from mice treated with GSL-liposomes produced higher levels of IFN-γ and IL-12 compared to mice that did not receive GSL-liposomes. Mice pretreated with GSL-liposomes showed low frequency of tumors after DMBA exposure. These findings suggest that co-administration of NKT cells activating GSL-liposomes and anti-cancer drug loaded liposomes may be proved a better option for the treatment of cancer.
PR1-specific cytotoxic T lymphocytes expanded from cord blood are functional in vitro (VAC11P.1002)
Authors: Wan Liping , St. John Lisa , He Hong , Clise-Dwyer Karen , Cooper Laurence , Sphall Elizabeth J , Bollard Catherine , Molldrem Jeffrey 
Published: January 2023

Abstract
Introduction Neutrophil elastase (NE) and proteinase 3 (P3) are serine proteases often found overexpressed in myeloid leukemic cells. PR1 is a nine amino acid, HLA-A2 restricted peptide derived from NE and P3. The frequency of PR1-specific T cells (PR1-CTL) is very low in healthy adult peripheral blood (0.0005 to 0.05% of CD8+ T cells), but much higher in umbilical cord blood (UCB) (0.007 to 0.345% of CD8+ T cells, N=57). We have previously shown sort-purified UCB PR1-CTL to be active against AML in a murine model. We now investigate the potential of UCB PR1-CTL to undergo expansion while maintaining the anti-leukemic properties of the cells. Methods HLA-A*0201 transfected K562 cells were loaded with PR1 peptide and irradiated with 3000 cGy. UCB mononuclear cells were stimulated with K562/A2/PR1 cells once a week for three weeks. CD8+ T cells were then negatively isolated from the expanded population by magnetic beads and underwent intracellular cytokine staining. Results Prior to expansion, the median percentage of PR1-CTL in the 9 UCB units tested was 0.211% (0.00%-0.348%) of CD8+ T cells. After stimulation this percentage increased to 0.958% (0.346%-2.1%). The expanded UCB PR1-CTL was of memory phenotype (CD45RA-/CCR7-). In addition, expanded UCB PR1-CTL produced both IFN-γ and TNF-α in response to PR1 peptide-loaded T2 cells. Conclusion PR1-CTL can be expanded from UCB and these expanded cells produce cytokines in a specific manner in response PR1-peptide loaded targets.