T cell-dependent elimination of dividingTrypanosoma grosifrom the bloodstream of Mongolian jirds

Parasitology ◽  
2004 ◽  
Vol 128 (3) ◽  
pp. 295-304 ◽  
Author(s):  
H. SATO ◽  
K. ISHITA ◽  
A. OSANAI ◽  
M. YAGISAWA ◽  
H. KAMIYA ◽  
...  
Keyword(s):  
Monoclonal Antibody ◽  
T Cells ◽  
T Cell ◽  
Serum Levels ◽  
Meriones Unguiculatus ◽  
T Cell Depletion ◽  
And Control ◽  
Kinetics Of ◽  
Peak Parasitaemia

Mongolian jirds,Meriones unguiculatus, are susceptible to infection withTrypanosoma grosi, which naturally parasitizesApodemusspp. The present study investigated T cell dependence of elimination ofT. grosifrom the bloodstream of jirds byin vivoT cell depletion using a monoclonal antibody (HUSM-M.g.15). In T cell-depleted jirds, elimination ofT. grosi, particularly the dividing forms, from the bloodstream was significantly delayed, occurring at around week 3 p.i. The kinetics of serum levels of IgM and IgG specific to trypanosomes in T cell-depleted and control immunocompetent jirds were different; peak levels of IgM were noted on days 6–8 p.i. around the time of peak parasitaemia (day 6 p.i.) in immunocompetent jirds, whereas the serum levels began to increase abruptly after day 10 p.i., peaking at around day 18 p.i. in T cell-depleted jirds. Similarly, serum IgG increased after day 6 p.i. in immunocompetent jirds, in contrast to after day 12 p.i. in T cell-depleted jirds, and the level increased steadily even after disappearance of parasitaemia. Our findings indicate that T cells play a major role at least in the ‘first crisis’ during elimination of dividingT. grosifrom the bloodstream.

scholarly journals A Novel Approach for the Treatment of T Cell Malignancies: Targeting T Cell Receptor Vβ Families

Vaccines ◽  
2020 ◽  
Vol 8 (4) ◽  
pp. 631
Author(s):  
Jie Wang ◽  
Katarzyna Urbanska ◽  
Prannda Sharma ◽  
Reza Nejati ◽  
Lauren Shaw ◽  
...  
Keyword(s):  
Monoclonal Antibody ◽  
T Cells ◽  
T Cell ◽  
T Cell Receptor ◽  
Cell Receptor ◽  
T Cell Lymphomas ◽  
Novel Approach ◽  
T Cell Malignancies

Peripheral T cell lymphomas (PTCLs) are generally chemotherapy resistant and have a poor prognosis. The lack of targeted immunotherapeutic approaches for T cell malignancies results in part from potential risks associated with targeting broadly expressed T cell markers, namely T cell depletion and clinically significant immune compromise. The knowledge that the T cell receptor (TCR) β chain in human α/β TCRs are grouped into Vβ families that can each be targeted by a monoclonal antibody can therefore be exploited for therapeutic purposes. Here, we develop a flexible approach for targeting TCR Vβ families by engineering T cells to express a chimeric CD64 protein that acts as a high affinity immune receptor (IR). We found that CD64 IR-modified T cells can be redirected with precision to T cell targets expressing selected Vβ families by combining CD64 IR-modified T cells with a monoclonal antibody directed toward a specific TCR Vβ family in vitro and in vivo. These findings provide proof of concept that TCR Vβ-family-specific T cell lysis can be achieved using this novel combination cell–antibody platform and illuminates a path toward high precision targeting of T cell malignancies without substantial immune compromise.

Host γd T cells Exacerbate Experimental Acute Graft-Versus-Host Disease through Activation of Host Antigen Presenting Cells.

Blood ◽  
2004 ◽  
Vol 104 (11) ◽  
pp. 3045-3045
Author(s):  
Yoshinobu Maeda ◽  
Pavan Reddy ◽  
Chen Liu ◽  
D. Keith Bishop ◽  
James L.M. Ferrara
Keyword(s):  
T Cells ◽  
T Cell ◽  
Mhc Class Ii ◽  
Graft Versus Host Disease ◽  
Serum Levels ◽  
Host Disease ◽  
Graft Versus Host ◽  
Full Intensity

Abstract Large numbers of T cells bearing γd T cell receptors are present in graft-versus-host disease (GVHD) target tissues. We investigated the potential role of host γd T cells during acute GVHD in a well-characterized GVHD model following full intensity conditioning (11 Gy TBI). BM and spleen T cells from BALB/c (H2d) donors were transplanted into wild type (wt) B6, aß T cell deficient B6 (aß −/−) or γd T cell deficient B6 (γd −/−) hosts. γd −/− hosts demonstrated significantly better day 35 survival (85%) than wt (40%) or aß−/− hosts (18%) (P<0.05). Reconstitution of γd −/− B6 hosts with B6 type γd T cells 24 hr prior to BMT restored lethal GVHD (50 % day 35 survival). In vivo, γd −/− B6 hosts demonstrated at least a five fold reduction in donor T cell expansion and cytokine production. In vitro, T cells proliferated less when co-cultured with allogeneic γd −/− dendritic cells (DCs) than with wt DCs (40,127 ± 1634 vs. 72,503 ± 1296, P<0.05). BM-derived DCs cultured with γd T cells caused greater proliferation of allogeneic T cells than DCs cultured with aß T cells (15.1 ± 21 x 104 vs. 5.1 ± 1.2 x 104, P<0.05). We next tested the effect of γd T cells on host DCs in vivo using a model system in which only the DCs injected prior to BMT expressed the alloantigen that stimulated the GVHD reaction. MHC Class II −/− B6 mice that had been depleted of γd T cells were given 11 Gy TBI and injected one day prior to BMT with B6 DCs that had been co-cultured either with γd T cells or with medium. On day 0 both groups of recipient mice were injected with BM plus splenic T cells from allogeneic bm12 donors. On day +5, CD4+ donor T cells expanded four times more in recipients of DCs co-cultured with γd T cells than in recipients of control DCs and serum levels of TNF-a were significantly higher (36.7 + 6.8 vs. 21.3 + 3.7 pg/ml, P<0.05). Together these data demonstrate that γd T cells amplify the stimulatory function of host DCs and increase the severity of GVHD, suggesting that a new therapeutic target for the prevention of the major BMT toxicity.

Reconstitution of CD52-Negative CD4 T Cells after Alemtuzumab-Based T Cell Depleted Allogeneic Hematopoietic Stem Cell Transplantation

Blood ◽  
2008 ◽  
Vol 112 (11) ◽  
pp. 1182-1182
Author(s):  
Eva M Wagner ◽  
Aline N Lay ◽  
Sina Wenzel ◽  
Timo Schmitt ◽  
Julia Hemmerling ◽  
...  
Keyword(s):  
Flow Cytometry ◽  
T Cells ◽  
T Cell ◽  
Cd4 T Cells ◽  
Lymphocytic Leukemia ◽  
Cell Depletion ◽  
Down Regulation ◽  
T Cell Depletion ◽  
Hematopoietic Stem

Abstract The human CD52 molecule is the target of the monoclonal antibody Alemtuzumab, which is used for treating patients with chemo-refractory chronic lymphocytic leukemia as well as for T cell depletion (TCD) in the context of allogeneic hematopoietic stem cell transplantation (HSCT). The molecule is expressed on the surface of lymphocytes, dendritic cells and to a lesser extent on blood-derived monocytes. Previously, investigators have demonstrated that the surface expression of CD52 on T cells is down-regulated after in vitro incubation with Alemtuzumab. By treating purified human CD4 T cells over 4 hours with 10 μg/mL Alemtuzumab in medium supplemented with 10% human AB serum in vitro, we observed a strong decrease of CD52 expression by flow cytometry with a maximum 3–7 days after incubation. The CD52 down-regulation was also found at weaker intensity on CD8 T cells. From previous studies in chronic lymphocytic leukemia patients, it is known that Alemtuzumab treatment also leads to a down-regulation of CD52 on T cells in vivo. However, similar experiments have not been performed in allogeneic HSCT patients receiving Alemtuzumab in vivo for T cell depletion. We therefore analyzed the expression of CD52 on human peripheral blood mononuclear cells isolated at repeated time points from 22 allogeneic HSCT patients after reduced-intensity conditioning with fludarabine and melphalan and in vivo T cell depletion with Alemtuzumab (100 mg). Half of the patients received prophylactic CD8-depleted donor lymphocyte infusions (DLI) to promote immune reconstitution. By flow cytometry, we observed that the CD52 expression on monocytes, B cells, and natural killer cells remained unaltered after transplantation and was not influenced by the application of DLI. In contrast, the majority of CD4 T cells were CD52-negative (median, 72%) after transplantation and they remained CD52-negative in patients who did not receive DLI throughout the first year after HSCT. The permanent lack of CD52 expression could not be explained by a continuous effect of Alemtuzumab, because earlier studies have shown that the antibody is not present in active plasma concentrations beyond day +60 after HSCT. In contrast, patients receiving CD8-depleted DLI demonstrated a significant increase in the proportion of CD52-positive CD4 T cells. In three of our patients (DLI: n=2, non-DLI: n=1) we analyzed the donor chimerism of CD52-positive and CD52-negative CD4 T cells sorted with high purity by flow cytometry. Three months after HSCT (before DLI), the proportion of donor T cells was clearly higher among the CD52-negative compared to the small proportion of CD52-positive cells in all patients (44% vs. 10%, 83% vs. 0%, and 100% vs. 40%). In the patient who did not receive DLI, the donor T cell chimerism remained mixed in the CD52-negative and CD52-positive fractions on days 200 (CD52-negative: 95%; CD52-positive: 15%) and 350 (CD52-negative: 92%; CD52-positive: 65%). In contrast, the two patients receiving CD8-depleted DLI showed a strong increase in the proportion of CD52-positive CD4 T cells that were of complete donor origin. Altogether, CD52 is permanently down-regulated in reconstituting CD4 T cells following HSCT with an Alemtuzumab-based TCD regimen unless DLI are applied. Our data support the idea of an active mechanism for CD52 down-regulation in CD4 T cells that is not related to B cells and natural killer cells and that appears to differently affect donor and host T cells, respectively.

Pentostatin Is Advantageous Relative to Fludarabine for in Vivo Murine T Cell Depletion, Suppression of T Cell Cytokine Secretion, and Inhibition of HVGR

Blood ◽  
2008 ◽  
Vol 112 (11) ◽  
pp. 3483-3483
Author(s):  
Jacopo Mariotti ◽  
Jason Foley ◽  
Kaitlyn Ryan ◽  
Nicole Buxhoeveden ◽  
Daniel Fowler
Keyword(s):  
T Cells ◽  
T Cell ◽  
Cd8 T Cells ◽  
Cytokine Secretion ◽  
Cell Depletion ◽  
T Cell Depletion ◽  
T Cell Suppression ◽  
Ifn Γ ◽  
Cell Suppression

Abstract Although fludarabine and pentostatin are variably utilized for conditioning prior to clinical allogeneic transplantation, limited data exists with respect to their relative efficacy in terms of host immune T cell depletion and T cell suppression. To directly compare these agents in vivo in a murine model, we compared a regimen of fludarabine plus cyclophosphamide (FC) similar to one that we previously developed (Petrus et al, BBMT, 2000) to a new regimen of pentostatin plus cyclophosphamide (PC). Cohorts of mice (n=5–10) received a three-day regimen consisting of P alone (1 mg/kg/d), F alone (100 mg/kg/d), C alone (50 mg/kg/d), or combination PC or FC. Similar to our previous data, administration of P, F, or C alone yielded minimal host T cell depletion (as measured by enumeration of splenic CD4+ and CD8+ T cells) and minimal T cell suppression (as determined by CD3, CD28 co-stimulation of a constant number of remaining splenic T cells and measuring resultant cytokine secretion by multi-analyte assay). The PC and FC regimens were similar in terms of myeloid suppression (p=.2). However, the PC regimen was more potent in terms of depleting host CD4+ T cells (remaining host CD4 number [× 10^6/spleen], 2.1±0.3 [PC] vs. 4.4±0.6 [FC], p<0.01) and CD8+ T cells (remaining host CD8 number, 1.7±0.2 [PC] vs. 2.4±0.5 [FC], p<0.01). Moreover, the PC regimen yielded greater T cell immune suppression than the FC regimen (cytokine values are pg/ml/0.5×10^6 cells/ml; all comparisons p<0.05) with respect to capacity to secrete IFN-γ (13±5 [PC] vs. 48±12 [FC]), IL-2 (59±44 [PC] vs. 258±32 [FC]), IL-4 (34±10 [PC] vs. 104±12 [FC]), and IL-10 (15±3 [PC] vs. 34±5 [FC]). In light of this differential in both immune T cell depletion and suppression of T cell effector function, we hypothesized that T cells from PC-treated recipients would have reduced capacity to mediate a host-versus-graft rejection response (HVGR) relative to FC-treated recipients. To directly test this hypothesis, we utilized a host T cell add-back model of rejection whereby BALB/c hosts were lethally irradiated (1050 cGy; day -2), reconstituted with host-type T cells from PC- or FC-treated recipients (day -1; 0.1 × 10^6 T cells transferred), and finally challenged with fully MHC-disparate transplantation (B6 donor bone marrow cells, 10 × 10^6 cells; day 0). In vivo HVGR was quantified by the following method at day 7 post-BMT: harvest of splenic T cells, stimulation with host- or donor-type dendritic cells, and use of six-color flow cytometry to detect host T cells, CD4 and CD8 subsets, and cytokine secretion by capture method. Consistent with our hypothesis, PC-treated cells acquired greatly reduced alloreactivity in vivo relative to FC-treated cells: the percentage of host CD4+ T cells secreting IFN-γ in an allospecific manner was 2.3±0.8% in recipients of PC-treated T cells and 62.7±13.4% in recipients of FC-treated cells (p<0.001). Similarly, the percentage of host CD8+ T cells secreting IFN-γ in an allospecific manner was 8.6±2.8% in recipients of PC-treated T cells and 92.7±4.1% in recipients of FC-treated T cells (p<0.001). We therefore conclude that at similar levels of myeloid suppression, the PC regimen is superior to the FC regimen in terms of murine T cell depletion, suppression of global T cell cytokine secretion, and inhibition of in vivo capacity to acquire allospecificity in response to fully genetically disparate marrow allografts. These data provide a rationale to develop PC regimens as an alternative to currently utilized FC regimens.

Cytokine and T-Cell Phenotypic Changes Upon In Vivo Ibrutinib Therapy For CLL – Targeting Both CLL Cells and The Tumor-Microenvironment

Blood ◽  
2013 ◽  
Vol 122 (21) ◽  
pp. 2856-2856 ◽  
Author(s):  
Carsten U Niemann ◽  
Angelique Biancotto ◽  
Betty Y. Chang ◽  
Joseph J. Buggy ◽  
J. Philip McCoy ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Inflammatory Cytokines ◽  
T Cell Activation ◽  
Serum Levels ◽  
Lymphocytic Leukemia ◽  
T Cell Subsets ◽  
Bcr Signaling ◽  
Pre Treatment

Abstract Introduction Proliferation of chronic lymphocytic leukemia (CLL) cells is highly dependent on the microenvironment. B-cell receptor (BCR) signaling and interactions of the tumor cells with elements of the tissue microenvironment including T cells and macrophages appear to be of particular importance (Burger et al, Blood 2009; Herishanu at al, Blood 2011; Bagnara at al, Blood 2011). The Bruton’s tyrosine kinase (BTK) inhibitor ibrutinib is highly effective in blocking BCR signaling and leads to impressive clinical responses in CLL (Byrd et al, NEJM 2013). BTK is a member of the TEC kinase family that also includes TEC, IL2-inducible T cell kinase (ITK), and BMX/ETK. BTK is not expressed in T cells; however ITK, which is expressed in T cells, is directly inhibited by ibrutinib, and the drug reduces cytokine secretion from activated T cells without inducing apoptosis (Herman et al, Blood, 2011). Here, we sought to determine the in vivo effect of ibrutinib on T cells and cytokine levels in CLL patients treated with single agent ibrutinib. Methods The effect of ibrutinib on T-cell subsets, T-cell activation, and cytokine profiles was assessed in 10 CLL patients treated with 420mg ibrutinib daily in an ongoing phase II trial (NCT01500733). Matched samples of viably frozen peripheral blood mononuclear cells obtained from patients pre-treatment and after 6 months on ibrutinib were analyzed by flow cytometry. Cytokine levels pre-treatment and on days 1, 28, months 2, and 6 on ibrutinib were measured in the same patients using the Milliplex human cytokine assay. Results Consistent with inhibition of BCR signaling in CLL cells, CCL3 and CCL4 serum levels were rapidly and significantly decreased by ibrutinib as described previously (Ponader et al, Blood, 2012). In addition, serum levels of a number of inflammatory cytokines including IL6, IL8, IFNg, and TNFα were decreased by > 50% by day 28 of ibrutinib treatment and remained so by 6 months. This is of specific interest as “pseudoexhausted” T cells from CLL patients were recently shown to secrete high amounts of IFNg, and TNFα (Riches et al, Blood 2013). Thus, the decreased levels of inflammatory cytokines may reflect a reversal of T cell “pseduoexhaustion”. Furthermore, the immunosuppressive cytokine IL10, a Th1-type cytokine that is secreted by CLL cells and activated T cells, was also rapidly and significantly reduced. These in vivo data are consistent with previous in vitro data showing decreased secretion of IL6 and IL10 from T cells upon exposure to ibrutinib (Herman et al, Blood, 2011). Thus, ibrutinib appears to reduce cytokine and chemokine secretion from both CLL and T cells resulting in an overall decrease in inflammatory cytokines. While absolute T-cell numbers showed little change on treatment, we found that ibrutinib reduced the frequency of activated CD4+ T cells (Table). Furthermore, for 3 out of 4 patients, the percentage of Ki67 positive T cells in the peripheral blood decreased on ibrutinib therapy (mean decrease 63%). The frequency of the Th17 T-cell subset was also diminished. Consistently, a decrease in serum levels of IL17 was seen in the two patients having detectable IL17 levels pre-treatment. While changes in the cytokine pattern (decrease in IFNg and IL10) might suggest inhibition of a Th1-type response, there was no change in the ratio of Th1 to Th2 T-cell subsets by immunophenotyping. Conclusions We here demonstrate a decrease in the levels of inflammatory cytokines and in T-cell activation in CLL patients treated with ibrutinib. Whether this is a direct consequence of BTK inhibition in B-cells or, at least in part, results from inhibition of T-cell signaling remains to be determined. Nevertheless, our data indicate that ibrutinib significantly alters the composition of the tumor microenvironment in CLL, affecting soluble as well as cellular elements. These effects may be important for clinical response and the development of combination therapies and therefore deserve further study. Supported by the Intramural Research Program of NHLBI. We thank our patients for participating and acknowledge Pharmacyclics for providing study drug. Disclosures: Off Label Use: Ibrutinib in chronic lymphocytic leukemia. Chang:Pharmacyclics: Employment, Equity Ownership. Buggy:Pharmacyclics: Employment, Equity Ownership.

The Use of Monoclonal Antibody Directed Chimeric Antigen Receptors to Facilitate Conventional T Cell and Treg Control of GvHD and Tissue Tolerance in Murine Models

Blood ◽  
2016 ◽  
Vol 128 (22) ◽  
pp. 3355-3355
Author(s):  
Antonio Pierini ◽  
Bettina Iliopoulou ◽  
Heshan Peiris ◽  
Magdiel Perez Cruz ◽  
Jeanette Baker ◽  
...  
Keyword(s):  
Monoclonal Antibody ◽  
T Cells ◽  
T Cell ◽  
Organ Transplantation ◽  
Adoptive Transfer ◽  
Skin Grafts ◽  
Mhc I ◽  
Cell Homing ◽  
University Patents

Abstract INTRODUCTION Regulatory T cells (Treg) modulate allograft immune responses and Treg-based cellular therapies can be used for prevention of graft-versus-host disease (GvHD) following hematopoietic cell transplantation and for prevention of allograft rejection following tissue or organ transplantation. Treg adoptive transfer has limitations including that Treg do not necessarily home to sites where they are needed and can become inactivated in inflammatory milieus. METHODS We used new technologies of T cell engineering to force the expression of a chimeric antigen receptor on T cells and Treg that recognizes labeled therapeutic monoclonal antibodies (mabCAR), allowing for precise control of their localization in vivo. The mabCAR recognizes fluorescein isothiocyanate (FITC) through a FITC-specific single-chain variable fragment fused to a CD28 and TCRζ costimulatory domain. Any monoclonal antibody (mab) coupled to FITC within its Fc domain can be recognized. We tested this approach with T cells and Treg to ameliorate GvHD and induce tolerance to pancreatic islet grafts. RESULTS We first tested our mabCAR construct in conventional T cells (Tcon) which when transfected and stimulated with a FITC-mab become activated and expressed higher levels of CD44 (p=0.0003), CD25 (p=0.009) and produced more IFNγ (p=0.04). To test if mabCAR transient transfection alters Tcon homing after adoptive transfer, we injected luc+ mabCAR Tcon directed against MAdCAM1 (a gut and lymph node endothelial integrin) or SDF1 (a chemokine mainly expressed in the bone marrow) into allogeneic hosts. MAdCAM1-directed Tcon mainly homed to the gut and lymph nodes, while SDF1-directed Tcon homed to bones and spleen. SDF1-directed Tcon induced a milder GvHD (p<0.001), demonstrating that cell homing impacts GvHD severity. We then tested mabCAR Treg ability to maintain their suppressive activity in vitro and in vivo. We found that mabCAR transiently transfected into Treg have increased ability to proliferate in response to anti-CD3/CD28 stimulatory beads (p<0.01) and highly suppress Tcon proliferation when co-cultured with allogeneic irradiated splenocytes. We injected MAdCAM1 directed Treg in an allogeneic GvHD model and these mabCAR Treg prolonged survival (p=0.03), improved GvHD score (p<0.001) and mouse weight profile (p<0.001), thus demonstrating that mabCAR Treg retain regulatory functions. Finally, we tested if mabCAR Treg could induce tolerance to allogeneic pancreatic islet grafts in sublethally irradiated hosts. Luc+gfp+ mabCAR Treg homed and expanded over time (p<0.05) to the site of the allogeneic islet grafts (right kidney capsule) when FITC-anti-allogeneic MHC-I mab directed the Treg as compared to isotype mab controls (see figure). Allo-MHC-I directed mabCAR-Treg prolonged allogeneic islet graft survival in comparison to isotype-mabCAR Treg (p=0.002) allowing for production of higher insulin levels. To assess if allo-MHC-I Treg promoted antigen-specific tolerance, we performed secondary skin graft transplantation. We found that mice which received MHC-I Treg showed a significant delay in the rejection of skin grafts from mice with the same MHC mismatch as the previous islet-allografts in comparison to third-party skin grafts (p=0.02) offering strong evidence that CAR-Treg could be used to enhance antigen-specific graft protection. CONCLUSION MabCAR expression can be used to control immune cell homing after transfer in different models according to localizing mab availability. We believe that the mabCAR approach may represent a new tool for optimizing cellular therapies to modulate GvHD and for inducing tolerance in islet and organ transplantation. Figure Figure. Disclosures Pierini: Stanford University: Patents & Royalties. Iliopoulou:Stanford University: Patents & Royalties. Negrin:Stanford University: Patents & Royalties. Kim:Stanford University: Patents & Royalties. Meyer:Stanford University: Patents & Royalties.

scholarly journals Effects of in Vivo Cd8+ T Cell Depletion on Virus Replication in Rhesus Macaques Immunized with a Live, Attenuated Simian Immunodeficiency Virus Vaccine

1999 ◽  
Vol 191 (11) ◽  
pp. 1921-1932 ◽  
Author(s):  
Karin J. Metzner ◽  
Xia Jin ◽  
Fred V. Lee ◽  
Agegnehu Gettie ◽  
Daniel E. Bauer ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Simian Immunodeficiency Virus ◽  
Cd8 T Cells ◽  
Rhesus Macaques ◽  
Cd8 T Cell ◽  
T Cell Depletion ◽  
Challenge Virus ◽  
Immunodeficiency Virus

The role of CD8+ T lymphocytes in controlling replication of live, attenuated simian immunodeficiency virus (SIV) was investigated as part of a vaccine study to examine the correlates of protection in the SIV/rhesus macaque model. Rhesus macaques immunized for &gt;2 yr with nef-deleted SIV (SIVmac239Δnef) and protected from challenge with pathogenic SIVmac251 were treated with anti-CD8 antibody (OKT8F) to deplete CD8+ T cells in vivo. The effects of CD8 depletion on viral load were measured using a novel quantitative assay based on real-time polymerase chain reaction using molecular beacons. This assay allows simultaneous detection of both the vaccine strain and the challenge virus in the same sample, enabling direct quantification of changes in each viral population. Our results show that CD8+ T cells were depleted within 1 h after administration of OKT8F, and were reduced by as much as 99% in the peripheral blood. CD8+ T cell depletion was associated with a 1–2 log increase in SIVmac239Δnef plasma viremia. Control of SIVmac239Δnef replication was temporally associated with the recovery of CD8+ T cells between days 8 and 10. The challenge virus, SIVmac251, was not detectable in either the plasma or lymph nodes after depletion of CD8+ T cells. Overall, our results indicate that CD8+ T cells play an important role in controlling replication of live, attenuated SIV in vivo.

A shift in encephalitogenic T cell cytokine pattern is associated with suppression of EAE by intravenous immunoglobulins (IVIg)

1997 ◽  
Vol 3 (2) ◽  
pp. 153-156 ◽  
Author(s):  
Anastas Pashov ◽  
Blanche Bellon ◽  
Srini V Kaveri ◽  
Michel D Kazatchkine
Keyword(s):  
T Cells ◽  
T Cell ◽  
Intravenous Immunoglobulins ◽  
Ivig Treatment ◽  
Autoimmune Encephalomyelitis ◽  
Proliferative Effect ◽  
Kinetics Of ◽  
Experimental Autoimmune

Pooled human polyspecific IgG preparations for intravenous use (IVIg) have been used in a number of antibody mediated autoimmune diseases and recently in some T cell mediated disorders including multiple sclerosis, birdshot retinopathy and rheumatoid arthritis. Furthermore, IVIg has been proven beneficial in the corresponding animal models, i.e. experimental autoimmune encephalomyelitis (EAE), experimental autoimmune uveoretinitis and adjuvant arthritis respectively. The exact mechanisms for IVIg adion in T cell mediated disorders are still poorly understood. There is evidence that IVIg treatment in vitro and in vivo decreases or changes the kinetics of the secretion by normal PBMC of a number of cytokines and anti-proliferative effect of IVIg on T cells in vitro and in vivo has also been reported. It remains unclear though to what extent the IVIg effects in T cell mediated autoimmunity are related only to non-specifc T cell suppression and whether it also reshapes the autoimmune T cell cytokine profile. In this study we demonstrate that IVIg protects against EAE and that this beneficial effed is associated with a decreased proli feration of T cells specific for the immunizing antigen. Moreover, we show that these antigen-specific cells produce low amount of Th /-type cytokines and transfer an attenuated EAE

Tumor-derived GDF-15 to suppress t-lymphocyte recruitment to the tumor microenvironment resulting in resistance to ANTI-PD-1 treatment.

2021 ◽  
Vol 39 (15_suppl) ◽  
pp. e14532-e14532
Author(s):  
Joerg Wischhusen ◽  
Markus Haake ◽  
Neha Vashist ◽  
Sabrina Genßler ◽  
Kilian Wistuba-Hamprecht ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Immune Cell ◽  
Serum Levels ◽  
Cell Infiltration ◽  
Immune Cell Infiltration ◽  
T Cell Infiltration ◽  
Melanoma Patients

e14532 Background: Growth and differentiation factor 15 (GDF-15) is a divergent member of the TGF-β superfamily with low to absent expression in healthy tissue. GDF-15 has been linked to feto-maternal immune tolerance, to prevention of excessive immune cell infiltration during tissue damage, and to anorexia. Various major tumor types secrete high levels of GDF-15. In cancer patients, elevated GDF-15 serum levels correlate with poor prognosis and reduced overall survival (OS). Methods: Impact of a proprietary GDF-15 neutralizing antibody (CTL-002) regarding T cell trafficking was analyzed by whole blood adhesion assays, a HV18-MK melanoma-bearing humanized mouse model and a GDF-15-transgenic MC38 model. Additionally, patient GDF-15 serum levels were correlated with clinical response and overall survival in oropharyngeal squamous cell carcinoma (OPSCC) and melanoma brain metastases. Results: In whole blood cell adhesion assays GDF-15 impairs adhesion of T and NK cells to activated endothelial cells. Neutralization of GDF-15 by CTL-002 rescued T cell adhesion. In HV18-MK-bearing humanized mice CTL-002 induced a strong increase in TIL numbers. Subset analysis revealed an overproportional enrichment of T cells, in particular CD8+ T cells. As immune cell exclusion is detrimental for checkpoint inhibitor (CPI) therapy, a GDF-15-transgenic MC38 model was tested for anti-PD-1 therapy efficacy. In GDF-15 overexpressing MC38 tumors response to anti PD-1 therapy was reduced by 90% compared to wtMC38 tumors. Combining aPD-1 with CTL-002 resulted in 50% of the mice rejecting their GDF-15 overexpressing tumors. Clinically, inverse correlations of GDF-15 levels with CD8+ T cell infiltration were shown for HPV+ OPSCC and for melanoma brain metastases. GDF-15 serum levels were significantly higher in HPV- than in HPV+ OPSCC patient (p < 0.0001). Low GDF-15 levels corresponded to longer OS in both HPV- and HPV+ OPSCC. In two independent melanoma patient cohorts treated with nivolumab or pembrolizumab low baseline serum GDF-15 levels were predictive for clinical response to anti-PD1 treatment and superior OS. Bivariate analysis including LDH indicates that GDF-15 independently predicts poor survival in aPD-1 treated melanoma patients. Conclusions: Taken together our in vitro and in vivo data show that elevated GDF-15 levels block T-cell infiltration into tumor tissues. Neutralizing GDF-15 with CTL-002 restores the ability of T cells to extravasate blood vessels and enter tumor tissue both in vitro and in vivo. In melanoma, patients with higher GDF-15 levels have significantly shorter survival and are less likely to respond to anti-PD1 therapy. GDF-15 may thus serve as a new predictive biomarker for anti-PD1 response, but most importantly also represents a novel target for cancer immunotherapy to improve tumor immune cell infiltration and response to anti-PD1 therapy.

Perforin and Fas Ligand Are Required for the Regulation of Alloreactive CD8+ T Cells.

Blood ◽  
2004 ◽  
Vol 104 (11) ◽  
pp. 3052-3052
Author(s):  
Yoshinobu Maeda ◽  
Robert B. Levy ◽  
Pavan Reddy ◽  
Chen Liu ◽  
Takanori Teshima ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Cd8 T Cells ◽  
Fas Ligand ◽  
Serum Levels ◽  
Cd8 T Cell ◽  
Rapid Decline ◽  
Target Cells ◽  
Donor T Cells

Abstract We evaluated the role of Fas ligand and perforin, the major T cell-mediated cytotoxic pathways that regulate T cell homeostasis, in a CD8+ T cell mediated model of graft-versus-host disease (GVHD) where donor and recipients differ at a single MHC class I antigen (B6 → bm1). Lethally irradiated (11Gy) bm1 mice were transplanted with T cell depleted BM and CD8+ T cells from either wild type (wt) or cytotoxic double deficient (cdd, deficient in both pathways) B6 donors. We hypothesized that cdd CD8+ T cells would be unable to mediate significant GVHD. Contrary to our hypothesis, recipients of cdd donor CD8+ T cells demonstrated significantly greater histopathologic damage from GVHD and increased serum levels of IFN-gamma and TNF-alpha compared to controls (Table 1). In order to understand this increase, we evaluated the in vivo expansion of donor T cells in these recipients as well as in BMT recipients of allogeneic CD8+ T cells from FasL deficient (gld) and perforin deficient (pfp−/−) donors. CD8+ wt T cells expanded until at day 10 after BMT, followed by a rapid decline. By contrast, cdd CD8+ T cells expanded continuously up to day 30 after BMT, peaking at almost one hundred times the number of wt T cells. gld T cells showed kinetics similar to wt T cells, whereas the pfp−/− T cells showed a significantly greater peak on day 10 but a similar contraction by day 30. Percentages of annexin+ cdd donor CD8+ T cells were significantly reduced compared to the other groups. Persistence of host antigen presenting cells did not account for the unrestrained expansion of cdd donor T cells because host dendritic cells were not detected in either the spleen, BM or gut of recipients of cdd CD8+ T cells on day 6 after BMT. In addition, alloantigen expression on epithelial target cells did not enhance GVHD because B6 donor cdd T cells induced equivalently lethal GVHD in [bm1 → B6] and [bm1 → bm1] chimeras (MST of 30 days and 27 days, respectively). We conclude that both perforin and Fas ligand pathways are required for alloreactive CD8+ T cell populations to contract after their initial expansion during a GVH reaction and that the absence of both these pathways results in donor CD8+ T cell unrestricted expansion and more severe GVHD. Table 1 GVHD score (gut) IFN-g (pg/ml) TNF-a (pg/ml) CD8+T cell (x10e6) Annexin+CD8+(%) cdd vs. wt, *P&lt;0.05 Wt 4.0±0.4 110±12 6.5±2.7 0.9±0.2 81±3.3 Cdd 5.7±0.3* 263±71* 64.6±3.2* 80.1±4.0* 62±3.6* Pfp−/− ND ND ND 2.6±0.7 73±5.1 Gld ND ND ND 1.7±0.4 80±0.6

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