scholarly journals Extracorporeal Photopheresis Therapy For Chronic Graft-Versus-Host Disease: Response Is Associated With Content Of Dendritic Cells And T-Cells In Peripheral Blood At Initiation Of Treatment

2009 ◽  
Vol 15 (2) ◽  
pp. 128-129
Author(s):  
M. Akhtari ◽  
C.R. Giver ◽  
H.M. Renfroe ◽  
A.A. Langston ◽  
H.J. Khoury ◽  
...  
Keyword(s):  
T Cells ◽  
Dendritic Cells ◽  
Graft Versus Host Disease ◽  
Peripheral Blood ◽  
Extracorporeal Photopheresis ◽  
Host Disease ◽  
Disease Response ◽  
Graft Versus Host

Higher Numbers of Circulating Dendritic Cells and T-Cells Predict Response to Extracorporeal Photopheresis in Patients with Chronic Graft-Versus-Host Disease

Blood ◽  
2008 ◽  
Vol 112 (11) ◽  
pp. 1183-1183
Author(s):  
Cynthia R. Giver ◽  
Mojtaba Akhtari ◽  
Amelia A. Langston ◽  
H. Jean Khoury ◽  
Christopher R. Flowers ◽  
...  
Keyword(s):  
T Cells ◽  
Dendritic Cells ◽  
T Cell ◽  
Median Time ◽  
Graft Versus Host Disease ◽  
Extracorporeal Photopheresis ◽  
Host Disease ◽  
Graft Versus Host ◽  
Cell Numbers ◽  
Hla Dr

Abstract Background: Therapeutic options for steroid-refractory chronic graft-versus-host-disease (cGVHD) are limited. Extracorporeal photopheresis (ECP) is a photoimmune therapeutic modality to treat cGVHD that is tolerated relatively well, but its mechanism has not been fully defined. One model for the mechanism of ECP in cGVHD is dendritic cell (DC) depletion and T-cell modification (Alcindor, T, et al., BLOOD2001, 98:1622). We tested this hypothesis by determining the numbers of circulating DCs and T-cells prior to ECP and during therapy in patients with cGVHD, and correlating cell numbers with response. Methods: This study was IRB approved. We studied 25 adult pts (median age 43 yrs, range 23–71) with histories of hematological malignancies including NHL (n=7), AML (n=5), CML (n=5), ALL (n=3), MDS (n=3), Hodgkin’s lymphoma (n=1), and CLL (n=1), who developed cGVHD after allogeneic, HLA-matched HPCT. Ten pts had progressive, 9 pts had de novo, and 6 pts had interrupted cGVHD. Initial treatment of cGVHD included corticosteroids in all pts. At the time of ECP initiation, pts were either dependent upon corticosteroids for control of cGvHD (21 pts), or steroid-intolerant (4 pts). No pts had received ECP prior to this study. ECP was administered 2 consecutive days every week for the first 2 months, two times a week every other week for 2 months, and then two times a week once a month. In addition to ECP, pts received steroids (21), MMF (n=13), FK506 (n=15), cyclosporine (n=3), MTX (n=3), rapamycin (n=1), rituximab (n=1) or pentostatin (n=1). Sites of cGVHD included skin (n=25), oropharynx (n=7), liver (n=5), gut (n=4), lung (n=1), and eye (n=1). A good response was defined as having > 50% reduction in the corticosteroid dose within 4 months of starting ECP, with improved or stable lesions on skin and other sites. For steroid-intolerant pts, clinical parameters such as improvement in skin condition were used to identify responders. Peripheral blood mononuclear cells were analyzed before ECP began and every 2 months during ECP therapy. The numbers of plasmacytoid DCs (pDC, Lin− CD123+ CD11c− HLA-DR+), myeloid DCs (mDC, Lin− CD123− CD11c+ HLA-DR+), and CD4+ and CD8+ T-cells in blood were determined by flow cytometry. Results: Median follow up of the 25 pts was 47.1 months (range, 8.6–90.9) from the time of transplant. The median number of ECP treatments was 26 (range 2–68). Fourteen pts (56%) had good response, and 11 were non-responders. The median time between HPCT and onset of cGVHD was similar for responders (8.6 months, range 3.3–34.7) and non-responders (6.1, range 3.4–43.8, p=0.52). The median time between HPCT and ECP was also similar for the two groups (32.3 months, range 13.1–60.0, vs. 21.9 months, range 4.1–47.5, respectively, p=0.12). Responders had an estimated 2-yr survival of 88% after starting ECP, vs 18% for non-responders (p=0.004). Two responders died at 11.2 and 31.2 months after starting ECP, compared with 7 non-responders (median 4.4 months, range 2.8–22.1). Non-responders had a relative risk of death of 11.6 compared with responders (p=0.022). Average prednisone doses for responders and non-responders were comparable, averaging 24.3 and 41.8 mg/day, respectively (p=0.11). Responders had higher baseline numbers of pDCs (average 5.8 vs. 0.6 cells/mcL, p=0.025) and mDCs (average 15 vs. 3.8 cells/mcL, p= 0.01) compared with non-responders. Baseline CD4+ T-cell numbers were higher in responders compared with non-responders (average 623 vs. 178 cells/mcL, p=0.005), as were CD8+ T-cell numbers (712 vs. 251 cells/mcL, p=0.047). Contrary to the original hypothesis, there were no consistent changes in the numbers of circulating DCs and T-cells among responders over a 12-month period. Receiver-operator characteristics (ROC) analysis showed that baseline numbers of blood mDCs of >3.7 cells/mcL prior to ECP had 79% sensitivity and 82% specificity to predict response of cGvHD patients to ECP. Conclusion: Our results demonstrate that higher numbers of circulating DCs and T-cells predict response to ECP in pts with cGVHD. Response to ECP was significantly associated with improved survival in univariate and multivariate analyses (p<0.03). Our findings support a newer model for the mechanism of response to ECP therapy, involving interactions between donor-derived DCs and donor T-cells. The generation of regulatory T-cells by dendritic cells presenting antigens from apoptotic bodies will be discussed.

scholarly journals IL-6 dysregulation originates in dendritic cells and mediates graft-versus-host disease via classical signaling

Blood ◽  
2019 ◽  
Vol 134 (23) ◽  
pp. 2092-2106 ◽  
Author(s):  
Andrew N. Wilkinson ◽  
Karshing Chang ◽  
Rachel D. Kuns ◽  
Andrea S. Henden ◽  
Simone A. Minnie ◽  
...  
Keyword(s):  
T Cells ◽  
Dendritic Cells ◽  
Graft Versus Host Disease ◽  
Host Disease ◽  
Graft Versus Host ◽  
Key Points ◽  
Donor T Cells ◽  
Principal Source

Key Points DCs are the principal source of IL-6 dysregulation after alloSCT. IL-6–dependent GVHD is driven by classical signaling of IL-6R on donor T cells but is regulated by trans signaling.

scholarly journals Expression of the T-Cell Activation Antigen, OX-40, Identifies Alloreactive T Cells in Acute Graft-Versus-Host Disease

Blood ◽  
1997 ◽  
Vol 89 (12) ◽  
pp. 4652-4658 ◽  
Author(s):  
Thomas V. Tittle ◽  
Andrew D. Weinberg ◽  
Cara N. Steinkeler ◽  
Richard T. Maziarz
Keyword(s):  
T Cells ◽  
T Cell Activation ◽  
Graft Versus Host Disease ◽  
Peripheral Blood ◽  
Cd4 T Cells ◽  
Cell Activation ◽  
Peripheral Blood Lymphocytes ◽  
Host Disease ◽  
Graft Versus Host ◽  
Acute Graft

Abstract The OX-40 molecule is expressed on the surface of recently activated T lymphocytes. The presence of OX-40 on CD4+ T cells was analyzed in a rat haplo-identical (parental → F1) bone marrow transplant model of acute graft-versus-host disease (aGVHD). Increased numbers of activated CD4+ T cells that expressed the OX-40 antigen were detected in peripheral blood soon after transplantation before the earliest sign of disease. The peak of OX-40 expression occurred 12 days posttransplantation with a range of 18% to 36% of circulating T cells and remained 10-fold above background, never returning to baseline. A slight increase in OX-40 expression (range, 1% to 6%) was also detected on peripheral blood lymphocytes from control syngeneic F1 → F1 recipients. OX-40+ T cells were isolated from spleen, skin, lymph node, and liver tissue of rats undergoing aGVHD, but not in syngeneic transplants. OX-40+ T cells isolated from these tissues were of donor origin and were shown to be allo-reactive. These data raise the possibility of using the OX-40 antibody to detect and deplete selectively the T cells that cause aGVHD.

Circulating B-cell activating factor level predicts clinical response of chronic graft-versus-host disease to extracorporeal photopheresis

Blood ◽  
2011 ◽  
Vol 118 (24) ◽  
pp. 6446-6449 ◽  
Author(s):  
Robert Whittle ◽  
Peter C. Taylor
Keyword(s):  
B Cell ◽  
Graft Versus Host Disease ◽  
Skin Disease ◽  
Therapeutic Option ◽  
Extracorporeal Photopheresis ◽  
Host Disease ◽  
Disease Response ◽  
Graft Versus Host ◽  
B Cell Activating Factor ◽  
Baff Level

Abstract Extracorporeal photopheresis (ECP) is an important therapeutic option in steroid-refractory chronic graft-versus-host disease (cGVHD). Few biomarkers predicting response exist. We measured serum B-cell activating factor (BAFF) in 46 cGVHD patients receiving ECP before and during treatment course. BAFF level at 1 month of ECP predicted 3- and 6-month skin disease response, with BAFF less than 4 ng/mL associated with significant skin improvement and complete resolution in 11 of 20 patients. High BAFF at 1-month ECP associated with a worsening median 6-month skin score and resolution in 1 of 10 patients. BAFF level at 3 months also predicted the likelihood of maintaining skin disease improvement at 6 months. BAFF level was not correlated directly with extracutaneous cGVHD response, although full cutaneous responders exhibited improved extracutaneous organ response rates compared with skin nonresponders (65% vs 35%). This study suggests that early BAFF measurement during ECP for cGVHD represents a potentially useful biomarker in prediction of treatment outcome.

Resting B Cells Suppress CD8+ T Cell Function and Prevent the Induction of Graft Versus Host Disease.

Blood ◽  
2005 ◽  
Vol 106 (11) ◽  
pp. 3111-3111
Author(s):  
David S. Ritchie ◽  
Victoria Watt
Keyword(s):  
T Cells ◽  
Dendritic Cells ◽  
T Cell ◽  
B Cells ◽  
Graft Versus Host Disease ◽  
Cd8 T Cell ◽  
Regulatory Function ◽  
In Vivo Models ◽  
Host Disease ◽  
Graft Versus Host

Abstract B cells have been variously shown to induce direct tolerance of antigen specific CD8+ T cells, induce T cell anergy via TGF-b production, down regulate IL-12 production by dendritic cells (DC) and influence Th1/Th2 differentiation via the production of regulatory cytokines. Through these mechanisms, B cells can exert a regulatory function in in vivo models of T cell immunity including, experimental autoimmune encephalitis (EAE) and rheumatoid arthritis (RA). Recently, B cells have been shown to be essential in the prevention of effector T cell differentiation in a model of autoimmunity. We have previously shown that resting B cells inhibited tumor protection induced by dendritic cells vaccination. Inhibition of DC immunity by B cells was independent of presentation of major histocompatibility molecule (MHC) class-I bound tumor antigen but dependent on the expression of class-II MHC. Furthermore the inhibitory effect of B cells was lost if the B cells were activated by CD40L or if CD4+/CD25+ regulatory T cells (Treg) were depleted. These studies have been further extended to examine the role of resting B cells on the induction and severity of graft versus host disease (GVHD) induced in a major MHC mismatch model. We have found that mice transplanted with B cell depleted marrow revealed more rapid CD8+ T cell engraftment, higher IL-2 and IFN-γ production, more severe GVHD and shorter survival. Conversely, those who received additional resting B cells at the time of marrow infusion were substantially protected from GVHD. These findings indicate that resting B cells may regulate T cell activation, in part via the suppressive effects of Treg, but also through their important role in T cell homeostasis. Resting B cells may therefore limit the efficacy of DC based immunotherapy or alternatively be used therapeutically to limit CD8+ T cell autoimmunity including GVHD.

Host Plasmacytoid or Conventional Dendritic Cells Alone Are Sufficient To Initiate Graft-Versus-Host Disease.

Blood ◽  
2007 ◽  
Vol 110 (11) ◽  
pp. 2164-2164
Author(s):  
Motoko Koyama ◽  
Daigo Hashimoto ◽  
Kazutoshi Aoyama ◽  
Ken-ichi Matsuoka ◽  
Kennosuke Karube ◽  
...  
Keyword(s):  
T Cells ◽  
Dendritic Cells ◽  
B Cells ◽  
Mhc Class Ii ◽  
Graft Versus Host Disease ◽  
Class Ii ◽  
Wild Type ◽  
Hematopoietic Stem ◽  
Host Disease ◽  
Graft Versus Host

Abstract Graft-versus-host disease (GVHD) is a major complication after allogeneic hematopoietic stem cell transplantation. Alloantigen expression on host dendritic cells (DCs) is critical to initiate GVHD. DCs can be divided into two main subpopulations; conventional DCs (cDCs) and plasmacytoid DCs (pDCs), however, the contribution of each DC subset to elicit GVHD remains unclear. We examined the ability of cDCs and pDCs to initiate GVHD. pDCs, cDCs and B cells were isolated from C57BL/6 (B6: H–2b) mice treated with Flt3 ligand in order to expand DCs. pDCs were enriched from bone marrow by depleting CD3+, CD19+, CD11b+, and CD49b+ cells, followed by a FACS sorting of CD11cint B220+ cells. cDCs and B cells were sorted from splenocytes as CD11chi B220− cells and CD11c− B220+ cells, respectively. Isolated pDCs showed plasmacytoid morphology, produced IFN-α in response to CpG oligonucleotide. Although pDCs stimulated allogeneic T cells far less potently than cDCs, stimulation with CpG enhanced their allostimulatory capacity as potent as cDCs. We compared the ability of each DC subset to initiate GVHD by an add-back study of MHC class II-expressing DCs into MHC class II-deficient (II−/−) mice that were resistant to CD4-dependent GVHD. Lethally irradiated II−/− B6 mice were injected with 2 × 106 pDCs, cDCs or B cells from wild-type (II+/+) B6 mice on day -1 and injected with 2 × 106 CD4+ T cell from BALB/c (H–2d) mice on day 0. A flow cytometric analysis of the mesenteric lymph nodes on day +5 demonstrated significantly greater expansion of donor CD4+ T cells in recipients of pDCs or cDCs than those of B cells (Table). While injection of B cells did not cause any sign of GVHD, injection of pDCs or cDCs alone was sufficient to produce clinical and pathological GVHD (Table), thus breaking GVHD resistance of II−/− mice. We next examined the ability of pDCs to induce CD8-dependent GVHD in MHC-matched transplant using mice deficient in functional MHC class I expression (β2m−/−). Again, injection of pDCs or cDCs alone was sufficient to cause expansion of donor CD8+ T cells (p<0.05). We next asked whether signaling through Toll-like receptors (TLRs) could be required for pDCs to initiate GVHD. However, injection of pDCs isolated from MyD88/TRIF-double deficient mice was able to initiate GVHD as potent as wild-type pDCs, thus demonstrating that pDCs initiate GVHD in a TLR signaling independent manner. These results provide important information for developing strategies aimed at inactivating host DCs to prevent GVHD. Impact of each APC subpopulation on GVHD APC Donor CD4 expansion (×103±SE) Clinical GVHD score (mean±SE) Pathological GVHD score (mean±SE) *p<0.05 compared with B cells B cell 0.1 ± 0.0 2.1 ± 0.2 2.1 ± 0.2 pDC 5.3 ± 2.4* 4.3 ± 0.3* 7.4 ± 0.5* cDC 9.7 ± 3.8 * 3.8 ± 0.5 * 7.2 ± 0.7*

Donor Dual TCR T Cells Preferentially Expand and Mediate Pathologic Alloreactivity in Acute Graft Versus Host Disease

Blood ◽  
2011 ◽  
Vol 118 (21) ◽  
pp. 1972-1972
Author(s):  
Gerald P. Morris ◽  
Geoffrey L Uy ◽  
David L Donermeyer ◽  
Paul M Allen ◽  
John F. DiPersio
Keyword(s):  
T Cells ◽  
T Cell ◽  
Graft Versus Host Disease ◽  
Peripheral Blood ◽  
Thymic Selection ◽  
Cell Repertoire ◽  
Host Disease ◽  
Graft Versus Host

Abstract Abstract 1972 The nature of the T cell repertoire mediating pathologic in vivo alloreactivity is an important question for understanding the development of acute graft-versus-host disease (aGvHD) following clinical allogeneic transplantation. We have previously demonstrated that the small proportion of T cells that naturally express 2 T cell receptors (TCR) as a consequence of incomplete TCRa allelic exclusion during thymic development contribute disproportionately to the alloreactive T cell repertoire, both in vitro and in vivo in a mouse model of graft versus host disease (GvHD) (J. Immunol., 182:6639, 2009). Here, we extend these findings to human biology, examining dual TCR T cells from healthy volunteer donors (n = 12) and patients who have undergone allogeneic hematopoietic stem cell transplantation (HSCT) (n = 19). Peripheral blood was collected at day 30 post-HSCT or at the time of presentation with symptomatic acute GvHD. Dual TCR T cells were measured in peripheral blood by pair-wise staining with 3 commercially-available and 2 novel TCRa mAbs. Dual TCR T cells were consistently and significantly expanded in patients with symptomatic aGvHD, representing 5.3±3.8 % of peripheral T cells, compared to 1.7±0.8 % of T cells in healthy controls (p < 0.005) (Figure 1). There was no correlation between dual TCR T cell frequency and GvHD severity. Furthermore, sequential analysis of peripheral blood in 2 patients demonstrated expansion of dual TCR T cells concurrent with the development of aGvHD (Figure 2). Dual TCR T cells from patients with symptomatic aGvHD demonstrated increased expression of CD69 as compared to T cells expressing a single TCR, indicative of preferential activation of dual TCR T cells during aGvHD. Similarly, dual TCR T cells isolated from patients with symptomatic aGvHD demonstrate increased production of IFN-g ex vivo, indicative of the ability to mediate pathogenic alloreactive responses. Dual TCR T cell clones isolated from healthy donors and patients post-HSCT by single cell FACS sorting demonstrate alloreactive responses against a range of allogeneic cell lines in vitro. We propose that the increased alloreactivity of dual TCR T cells results from the less stringent thymic selection for secondary TCR, and thus provides a link between thymic selection, the TCR repertoire, and alloreactivity. These findings may lead to simple ways of phenotypically identifying specific T cells predisposed to inducing aGvHD for subsequent examination of T cell repertoires and functional studies. Furthermore, these data suggest that dual TCR T cells represent a potential predictive biomarker for aGvHD and a potential target for selective T cell depletion in HSCT. Disclosures: No relevant conflicts of interest to declare.

Chimerism, Lymphocyte Recovery, and the Absence of Graft-Versus-Host Disease in Recipients of Mismatched Unrelated Combined Kidney and HSC Transplants for Tolerance Induction

Blood ◽  
2011 ◽  
Vol 118 (21) ◽  
pp. 1969-1969
Author(s):  
Joseph Leventhal ◽  
Paul A Cardenas ◽  
Mary J Elliott ◽  
Suzanne T Ildstad
Keyword(s):  
T Cells ◽  
Stem Cell ◽  
Graft Versus Host Disease ◽  
Peripheral Blood ◽  
Living Donor ◽  
Renal Transplant Recipients ◽  
Host Disease ◽  
Graft Versus Host ◽  
Post Transplant

Abstract Abstract 1969 Background: It has been known for over 50 years that hematopoietic stem cell (HSC) chimerism induces tolerance to transplanted tissues and cells. However, the widespread application of this approach has been constrained by graft-versus-host disease (GVHD), the need for close genetic matching between donor and recipient, and the toxicity of conditioning the recipient to establish chimerism. We have demonstrated that full donor chimerism can be established with minimal toxicity in highly-mismatched unrelated and related kidney allograft recipients through nonmyeloablative conditioning followed by infusion of a bioengineered CD8+/TCR− facilitating cell stem cell graft (FCRx), to avoid the risk of GVHD while achieving chimerism. Methods: Twelve HLA-mismatched living donor renal transplant recipients have been entered into a phase 2 trial (IDE 13947) involving low-intensity conditioning (fludarabine, cyclophosphamide, 200 cGy TBI days −4 to −1). Patients received a living donor kidney transplant on day 0, followed by infusion of G-CSF cryopreserved FCRx on day +1. All subjects were discharged by post-operative day 3 and managed as outpatients. We herein present data regarding the immunologic recovery observed in our first 8 evaluable patients with > 6 months follow up. Results: All patients experienced an expected nadir period affecting leukocytes (ANC < 500, range 2–14 days) and platelets (< 50K, range 0–20 days). All patients demonstrated peripheral blood macrochimerism at 1 month post-transplant, ranging from 6% to 100%. Chimerism was gradually lost in two patients at 3 and 6 months post-transplant. Patients demonstrated in vitro evidence of donor-specific hyporesponsiveness (DSH) by MLR +/− CML as early as 3 months post-transplant; of interest, DSH also was observed and persisted in the two patients who lost peripheral blood chimerism. Patients at > 1 yr post-transplant are immunocompetent to respond to mitogen (PHA), MHC-disparate third-party alloantigen, and tetanus in in vitro proliferative assays. Immunologic reconstitution in kidney + FCRx recipients was characterized by a blunted return in CD4+ T cells, with inversion of the CD4/CD8 ratio. A preferential recovery of memory (CD4+/CD45RO+/CD62L+/−) vs. naïve (CD4+/CD45RA+/CD62L+) T cells was observed. Although total number of CD4+/CD25+/CD127lo/FoxP3+ Treg was reduced initially, an increase in the CD4+ Treg /CD4+Teff (CD4+/CD45RA+/CD62L−) ratio was seen in patients exhibiting durable chimerism. In addition, an expansion of central memory CD8+ T cells was observed in durably chimeric recipients. No patient developed donor-specific antibodies as assessed by flow cytometric analysis. The absence of GVHD correlated with in vitro hyporesponsiveness of the fully chimeric recipients against archived pre-treatment recipient APC. Conclusions: Combined kidney + FCRx recipients demonstrate characteristic immunophenotypic and functional changes associated with reconstitution following transplantation; additional studies are required to determine whether these changes are mechanistically related to the persistence of chimerism and/or prevention of GVHD. Disclosures: Ildstad: Regenerex LLC: Equity Ownership.

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