Non-Myeloablative Conditioning of Total Lymphoid Irradiation (TLI) and Anti-Thymocyte Globulin (ATG) Protects Against Acute GVHD Following Allogeneic Hematopoietic Cell Transplantation (HCT) but Retains Anti-Tumor Activity.

Blood ◽  
2004 ◽  
Vol 104 (11) ◽  
pp. 433-433
Author(s):  
Robert Lowsky ◽  
Tsuyoshi Takahashi ◽  
Yin Ping ◽  
Judith Shizuru ◽  
Robert S. Negrin ◽  
...  
Keyword(s):  
T Cells ◽  
Cd8 T Cells ◽  
Cell Subset ◽  
Lymphocytic Leukemia ◽  
Hematopoietic Cell ◽  
Lymphoid Tissues ◽  
Advanced Stage ◽  
Stage Disease ◽  
Nk T Cells ◽  
Anti Tumor Activity

Abstract Separation of GVHD from graft versus tumor (GVT) reactions is critical in improving outcomes for HCT. Murine models of transplantation showed that after conditioning with repeated low doses of irradiation targeted to lymphoid tissues (TLI) are combined with ATG, regulatory natural killer (NK) T cells become the predominant T cell subset. Secretion of high levels of IL-4 by the host NK T cells protects against aGVHD following HCT. Yet tumor killing activity mediated by donor CD8+ T cells via a direct cytolytic pathway involving perforin remains intact. Thus, regulatory T cells can separate GVHD from graft anti-tumor activity. We adapted the murine protocol to a clinical regimen of TLI (10 doses of 80 cGy/dose) and rabbit ATG (5 doses of 1.5 mg/kg/dose) with post-grafting immunosuppression of mycophenylate mofetil (MMF) and cyclosporin (CSP) to determine if the regimen separates aGVHD from GVT reactions in humans. In a completed phase I and an ongoing phase II study 37 patients with extensively pretreated hemato-lymphoid malignancies (22 with lymphoma, 4 with lymphocytic leukemia and 11 with AML) received related (23) or unrelated (14) HLA matched G-CSF mobilized HCT. Twenty nine patients (78%) had advanced stage disease, 12 had received prior autologous transplants, 18 were in a partial remission (PR) at the time of allogeneic transplant, 2 had progressive disease (PD) and 17 were in complete remission (CR). All patients had initial multilineage donor hematopoietic cell engraftment within 56 days post transplantation. The median follow-up (F/U) for all patients is 262 days with 27 of 37 patients alive. Thirty six of 37 patients had grade 0 aGVHD and 1 patient had grade III aGVHD that responded to steroid therapy. Thirty-five patients were alive at day 100 and considered at risk for cGVHD. Six of the 35 developed denovo extensive cGVHD, and one developed extensive cGVHD following aGVHD. Twenty-eight patients had either no or limited cGVHD. Of the 18 patients transplanted in PR, 11 achieved a CR and have not relapsed, 2 did not clear their tumor, 2 are too early to evaluate and 3 died from non-relapse causes. Eleven of 16 patients transplanted in CR continue in CR and of the 5 that relapsed all had advanced stage disease. Evaluation of sorted CD4+ T cells obtained 1–6 months after HCT from fully chimeric recipients conditioned with TLI/ATG showed a statistically significant increase in IL-4 secretion following in vitro stimulation, and a statistically significant decrease in the proliferation response to allogeneic stimulator cells in the mixed leukocyte reaction (MLR) as compared to normal controls or to patients given non-myeloablative TBI conditioning. Sorted CD8+ T cells obtained from TLI/ATG conditioned patients retained vigorous cytolytic activity in the cell mediated lympholysis (CML) assay. In conclusion, TLI/ATG conditioning resulted in a markedly reduced incidence of aGVHD but with retained GVT reactions as the majority of patients with PR converted to CR and did not relapse. We show evidence that as in the pre-clinical model the low incidence of GVHD is associated with increased IL-4 secretion by chimeric donor T cells and a reduced proliferative response to alloantigens but retained anti-tumor activity.

Haploidentical Non-Myeloablative Allogeneic Hematopoietic Cell Transplantation (HCT) Using Total Lymphoid Irradiation (TLI) and Anti-Thymocyte Globulin (ATG) Conditioning Protects Against Acute Graft Versus Host Disease (GVHD).

Blood ◽  
2005 ◽  
Vol 106 (11) ◽  
pp. 2904-2904 ◽  
Author(s):  
R. Lowsky ◽  
K. Heydari ◽  
B. Sahaf ◽  
J. Shizuru ◽  
G. Laport ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Acute Gvhd ◽  
Absolute Number ◽  
Hematopoietic Cell ◽  
T Cell Subsets ◽  
Cell Dose ◽  
Cell Engraftment ◽  
Nk T Cells ◽  
Anti Tumor Activity

Abstract Murine models of transplantation established that nonmyeloablative conditioning using repeated low doses of irradiation targeted to lymphoid tissues (TLI) and depletive anti-T cell antibodies protects against GVHD by skewing residual host T cell subsets to favor regulatory natural killer (NK) T cells that suppress GVHD by polarizing donor T cells toward secretion of non-inflammatory cytokines such as IL-4. We recently translated the murine protocol to a clinical study using non-myeloablative TLI and ATG host conditioning with HLA matched related and unrelated donors, and showed a marked reduction in the incidence of acute GVHD while retaining graft anti-tumor activity (Lowsky et al., in Press NEJM). Engrafted donor CD4+ T cells showed a marked increase in IL-4 production as compared to CD4+ T cells from controls. We now adapted the TLI and ATG nonmyeloablative host conditioning regimen to a clinical study of allogeneic HCT using haploidentical matched (3/6 HLA matched) related donors to determine if it will result in donor hematopoietic cell engraftment and also protect against acute GVHD. Blood derived hematopoietic progenitor cells were collected by apheresis from donors mobilized with G-CSF and the product was T cell depleted using CD34+ selection. CD3+ T cells were added back to the donor inoculum according to a dose escalation schedule. The initial T cell dose was 1 x105 CD3+ cell/kg with designated increments based on clinical outcomes of up to a maximum of 1 x107 CD3+ cells/kg. The desired CD34+ cell dose was >5 x 106 CD34+ cells/kg for all patients. Seven patients were transplanted; the median age was 53 years (range 27 to 61 years). Five patients had acute myelogenous leukemia, two with disease in remission and three not in remission at the start of TLI and ATG, one with myelodysplastic syndrome, and one with progressive peripheral T cell lymphoma. The median follow-up for all patients is 265 days with three of seven patients alive and free of disease at the last observation period. Sustained donor hematopoietic cell engraftment was achieved in three of three patients only after the T cell dose was increased to 1 x107 CD3+ cells/kg. No patient developed acute GVHD. None of the three patients receiving the highest dose of T cells had any invasive fungal or viral infections. Monitoring of sorted host T cell subsets before TLI and ATG, and immediately after but before the infusion of donor cells, revealed in five of five patients a highly significant skewing of residual host T cells favoring invariant NK T (CD3+ CD161hi Va24 +Vb11 +) cells. The mean absolute number of host CD3+, and CD4+ and CD8+ T cells decreased by 99, 163 and 121 fold, respectively, immediately after conditioning compared to the absolute numbers before the start of TLI and ATG, whereas the mean absolute number of invariant NK T cells decreased by only 11%. In conclusion, we have determined the conditions for successful hematopoietic cell engraftment using a non-myeloablative regimen of TLI and ATG that appears associated with a reduced aGVHD risk yet retained graft anti-tumor activity. As in the pre-clinical model, we show direct evidence that the low incidence of aGVHD is associated with a significant alteration in residual host T cell subsets markedly favoring invariant NK T cells.

Oligoclonal TCRBV Gene Usage in B-Cell Chronic Lymphocytic Leukemia: Major Perturbations Are Preferentially Seen Within the CD4 T-Cell Subset

Blood ◽  
1999 ◽  
Vol 94 (3) ◽  
pp. 1063-1069 ◽  
Author(s):  
Mohammad-Reza Rezvany ◽  
Mahmood Jeddi-Tehrani ◽  
Anders Österborg ◽  
Eva Kimby ◽  
Hans Wigzell ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Cd8 T Cells ◽  
Cell Subset ◽  
Lymphocytic Leukemia ◽  
Cd4 T Cell ◽  
Cdr3 Length ◽  
Significant Difference ◽  
Gene Usage ◽  
Cell Chronic Lymphocytic Leukemia

TCRBV (T-cell receptor B variable) gene usage and CDR3 size distribution were analyzed using reverse transcription polymerase chain reaction (RT-PCR) to assess the T-cell repertoire of 10 patients with B-cell chronic lymphocytic leukemia (B-CLL) and in nine age-matched healthy control donors. When the usage of each TCRBV gene within the CD8+ T cells of the patients was compared with that of the controls, no statistically significant difference was noted except for BV 6S1-3. In contrast, within the CD4+ T cells of the CLL patients, a statistically significant overexpression for four BV families (2, 3, 5S1, 6S1-3) was seen while an underrepresentation was noted for five BV families (10, 11, 15, 16, 19). Based on the criterion that a value of any BV higher than the mean + 3 standard deviation (SD) of healthy controls indicated an overexpression, individual patients were shown to overexpress several TCRBV genes compared with the controls. Analyses of the CDR3 length polymorphism showed a significantly higher degree of restriction within CD4+ and CD8+ T cells of the patients, as compared with the corresponding control T-cell population. There was a significant difference in the CDR3 size distribution pattern with a more polymorphic CDR3 length pattern in the age-matched controls as compared with CLL patients, suggesting different mechanisms driving the T cells towards a clonal/oligoclonal TCRBV usage in patients and controls, respectively. The results show major perturbations of T cells in CLL patients, more frequently seen in the CD4+ T-cell subset, indicating that nonmalignant CD4+ T cells may be involved in the pathogenesis of CLL, but also CD8+ T cells.

Control of chronic lymphocytic leukemia development by clonally-expanded CD8+ T-cells that undergo functional exhaustion in secondary lymphoid tissues

Leukemia ◽  
2018 ◽  
Vol 33 (3) ◽  
pp. 625-637 ◽  
Author(s):  
Bola S. Hanna ◽  
Philipp M. Roessner ◽  
Haniyeh Yazdanparast ◽  
Dolors Colomer ◽  
Elias Campo ◽  
...  
Keyword(s):  
T Cells ◽  
Chronic Lymphocytic Leukemia ◽  
Cd8 T Cells ◽  
Lymphocytic Leukemia ◽  
Lymphoid Tissues ◽  
Functional Exhaustion ◽  
Leukemia Development

scholarly journals Targeting CD38 is lethal to Breg-like chronic lymphocytic leukemia cells and Tregs, but restores CD8+ T-cell responses

2020 ◽  
Vol 4 (10) ◽  
pp. 2143-2157 ◽  
Author(s):  
Alak Manna ◽  
Timothy Kellett ◽  
Sonikpreet Aulakh ◽  
Laura J. Lewis-Tuffin ◽  
Navnita Dutta ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Chronic Lymphocytic Leukemia ◽  
Cd8 T Cells ◽  
Mononuclear Cells ◽  
Transforming Growth Factor ◽  
Ex Vivo ◽  
Xenograft Model ◽  
Lymphocytic Leukemia ◽  
Dependent Manner

Abstract Patients with chronic lymphocytic leukemia (CLL) are characterized by monoclonal expansion of CD5+CD23+CD27+CD19+κ/λ+ B lymphocytes and are clinically noted to have profound immune suppression. In these patients, it has been recently shown that a subset of B cells possesses regulatory functions and secretes high levels of interleukin 10 (IL-10). Our investigation identified that CLL cells with a CD19+CD24+CD38hi immunophenotype (B regulatory cell [Breg]–like CLL cells) produce high amounts of IL-10 and transforming growth factor β (TGF-β) and are capable of transforming naive T helper cells into CD4+CD25+FoxP3+ T regulatory cells (Tregs) in an IL-10/TGF-β-dependent manner. A strong correlation between the percentage of CD38+ CLL cells and Tregs was observed. CD38hi Tregs comprised more than 50% of Tregs in peripheral blood mononuclear cells (PBMCs) in patients with CLL. Anti-CD38 targeting agents resulted in lethality of both Breg-like CLL and Treg cells via apoptosis. Ex vivo, use of anti-CD38 monoclonal antibody (mAb) therapy was associated with a reduction in IL-10 and CLL patient-derived Tregs, but an increase in interferon-γ and proliferation of cytotoxic CD8+ T cells with an activated phenotype, which showed an improved ability to lyse patient-autologous CLL cells. Finally, effects of anti-CD38 mAb therapy were validated in a CLL–patient-derived xenograft model in vivo, which showed decreased percentage of Bregs, Tregs, and PD1+CD38hiCD8+ T cells, but increased Th17 and CD8+ T cells (vs vehicle). Altogether, our results demonstrate that targeting CD38 in CLL can modulate the tumor microenvironment; skewing T-cell populations from an immunosuppressive to immune-reactive milieu, thus promoting immune reconstitution for enhanced anti-CLL response.

IL-8 responsiveness defines a subset of CD8 T cells poised to kill

Blood ◽  
2004 ◽  
Vol 104 (12) ◽  
pp. 3463-3471 ◽  
Author(s):  
Christoph Hess ◽  
Terry K. Means ◽  
Patrick Autissier ◽  
Tonia Woodberry ◽  
Marcus Altfeld ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Chemokine Receptor ◽  
Cd8 T Cells ◽  
Molecular Mechanisms ◽  
Cell Subset ◽  
Cd8 T Cell ◽  
Effector Memory ◽  
Immune System Activation ◽  
Hiv 1

CD8 T cells play a key role in host defense against intracellular pathogens. Efficient migration of these cells into sites of infection is therefore intimately linked to their effector function. The molecular mechanisms that control CD8 T-cell trafficking into sites of infection and inflammation are not well understood, but the chemokine/chemokine receptor system is thought to orchestrate this process. Here we systematically examined the chemokine receptor profile expressed on human CD8 T cells. Surprisingly, we found that CXC chemokine receptor 1 (CXCR1), the predominant neutrophil chemokine receptor, defined a novel interleukin-8/CXC ligand 8 (IL-8/CXCL8)–responsive CD8 T-cell subset that was enriched in perforin, granzyme B, and interferon-γ (IFNγ), and had high cytotoxic potential. CXCR1 expression was down-regulated by antigen stimulation both in vitro and in vivo, suggesting antigen-dependent shaping of the migratory characteristics of CD8 T cells. On virus-specific CD8 T cells from persons with a history of Epstein-Barr virus (EBV) and influenza infection, CXCR1 expression was restricted to terminally differentiated effector memory cells. In HIV-1 infection, CXCR1-expressing HIV-1–specific CD8 T cells were present only in persons who were able to control HIV-1 replication during structured treatment interruptions. Thus, CXCR1 identifies a subset of CD8 T cells poised for immediate cytotoxicity and early recruitment into sites of innate immune system activation.

scholarly journals Human CD8+ T-cells Recognizing Peptides from Mycobacterium tuberculosis (Mtb) Presented by HLA-E Have an Unorthodox Th2-like, Multifunctional, Mtb Inhibitory Phenotype and Represent a Novel Human T-cell Subset

2015 ◽  
Vol 11 (3) ◽  
pp. e1004671 ◽  
Author(s):  
Krista E. van Meijgaarden ◽  
Mariëlle C. Haks ◽  
Nadia Caccamo ◽  
Francesco Dieli ◽  
Tom H. M. Ottenhoff ◽  
...  
Keyword(s):  
T Cells ◽  
Mycobacterium Tuberculosis ◽  
T Cell ◽  
Cd8 T Cells ◽  
Cell Subset ◽  
T Cell Subset ◽  
Human T Cell

Cognate CD4 help is essential for the reactivation and expansion of CD8 memory T cells directed against the hematopoietic cell–specific dominant minor histocompatibility antigen, H60

Blood ◽  
2009 ◽  
Vol 113 (18) ◽  
pp. 4273-4280 ◽  
Author(s):  
Su Jeong Ryu ◽  
Kyung Min Jung ◽  
Hyun Seung Yoo ◽  
Tae Woo Kim ◽  
Sol Kim ◽  
...  
Keyword(s):  
T Cells ◽  
Cd8 T Cells ◽  
Primary Response ◽  
Hematopoietic Cell ◽  
Secondary Response ◽  
Memory Cd8 T Cells ◽  
Specific Memory ◽  
Cd4 Help ◽  
Different Response

AbstractIn contrast to previous notions of the help-independency of memory CD8 T cells during secondary expansion, here we show that CD4 help is indispensable for the re-expansion of once-helped memory CD8 T cells, using a hematopoietic cell–specific dominant minor histocompatibility (H) antigen, H60, as a model antigen. H60-specific memory CD8 T cells generated during a helped primary response vigorously expanded only when rechallenged under helped conditions. The help requirement for an optimal secondary response was confirmed by a reduction in peak size by CD4 depletion, and was reproduced after skin transplantation. Helpless conditions or noncognate separate help during the secondary response resulted in a significant reduction in the peak size and different response kinetics. Providing CD4 help again during a tertiary challenge restored robust memory expansion; however, the repeated deprivation of help further reduced clonal expansion. Adoptively transferred memory CD8 T cells did not proliferate in CD40L−/− hosts. In the CD40−/− hosts, marginal memory expansion was detected after priming with male H60 cells but was completely abolished by priming with peptide-loaded CD40−/− cells, suggesting the essential role of CD40 and CD40L in memory responses. These results provide insight into the control of minor H antigen-specific CD8 T-cell responses, to maximize the graft-versus-leukemia response.

scholarly journals Mechanisms regulating IgA class-specific immunoglobulin production in murine gut-associated lymphoid tissues. II. Terminal differentiation of postswitch sIgA-bearing Peyer's patch B cells.

1983 ◽  
Vol 158 (3) ◽  
pp. 649-669 ◽  
Author(s):  
H Kawanishi ◽  
L Saltzman ◽  
W Strober
Keyword(s):  
T Cells ◽  
T Cell ◽  
B Cells ◽  
Present Report ◽  
Protein A ◽  
Cell Subset ◽  
Terminal Differentiation ◽  
Lymphoid Tissues ◽  
T Cell Subset ◽  
Iga Production

Our previous studies indicated that cloned T cells obtained from Peyer's patches (PP) (Lyt-1+, 2-, Ia+, and H-2K/D+) evoked immunoglobulin (Ig) class switching of PP B cells from sIgM to sIgA cells in vitro; however, these switch T cells could not in themselves provide optimal help for the differentiation of postswitch sIgA-bearing PP B cells to IgA-secreting cells. Thus, in the present report we described studies focused on mechanisms regulating terminal differentiation of the postswitch PP sIgA-bearing B cells. First, to explore the effect of T cell-derived B cell differentiation factor(s) (BCDF) and macrophage factor(s) (MF) on the terminal maturation of PP B cells, LPS-stimulated PP B cells were co-cultured for 7 d with cloned T cells in the presence or absence of the above factors. In the absence of PP cloned T cells the BCDF and MF had only a modest effect on IgA production, whereas in the presence of PP, but not spleen cloned T cells, IgA production was increased. Next, to investigate the effect of T cells derived from a gut-associated lymphoid tissue (GALT), mesenteric lymph nodes (MLN), as well as from spleen on terminal differentiation of postswitch sIgA PP B cells, LPS-driven PP B cells were precultured with the cloned T cells to induce a switch to sIgA, and subsequently cultured with MLN or spleen T cells or a Lyt-2+-depleted T cell subset in the presence of a T-dependent polyclonal mitogen, staphylococcal protein A. Alternatively, in the second culture period BCDF alone was added, instead of T cells and protein A. Here it was found that B cells pre-exposed to switch T cells from PP, but not spleen, were induced to produce greatly increased amounts of IgA in the presence of protein A and T cells or a Lyt-2+-depleted T cell subset as well as in the presence of BCDF alone. Furthermore, in the presence of BCDF alone many B cells expressed cytoplasmic IgA. These observations strongly support the view that the terminal differentiation of postswitch sIgA B cells is governed by helper T cells and macrophages, or factors derived from such cells. Such cells or factors do not affect preswitch B cells.

scholarly journals Development of an IL-15–autocrine CD8 T-cell leukemia in IL-15–transgenic mice requires the cis expression of IL-15Rα

Blood ◽  
2011 ◽  
Vol 117 (15) ◽  
pp. 4032-4040 ◽  
Author(s):  
Noriko Sato ◽  
Helen Sabzevari ◽  
Song Fu ◽  
Wei Ju ◽  
Michael N. Petrus ◽  
...  
Keyword(s):  
T Cells ◽  
Transgenic Mice ◽  
Cd8 T Cells ◽  
Constitutive Expression ◽  
Γδ T Cells ◽  
Selective Advantage ◽  
Intraepithelial Lymphocytes ◽  
Leukemic Transformation ◽  
Nk T Cells ◽  
Growth Promoting

AbstractIL-15 has growth-promoting effects on select lymphoid subsets, including natural killer (NK) cells, NK T cells, intraepithelial lymphocytes (IELs), CD8 T cells, and γδ-T cells. Constitutive expression of murine IL-15 in IL-15–transgenic mice was reported to cause T-NK leukemia. We investigated whether IL-15 expression is sufficient for leukemic transformation using a human IL-15–transgenic (IL-15Tg) mouse model. We noted that 100% of the mice observed over a 2-year period (n > 150) developed fatal expansions of CD8 T cells with NK markers, and determined that these cells expressed IL-15 receptor alpha (IL-15Rα). The expression of IL-15Rα on CD8 T cells appears to be required for uncontrolled aggressive lymphoproliferation, because none of the IL-15Rα−/−–IL-15Tg mice that we followed for more than 2 years developed the fatal disease despite controlled expansion of CD8 T cells. In addition, in contrast to IL-15Tg mice, in which leukemia-like CD8 T cells expressed IL-15Rα persistently, acutely activated normal CD8 T cells only transiently expressed IL-15Rα. Inhibition of DNA methylation enabled sustained IL-15Rα expression induced by activation. We present a scenario for IL-15Tg mice in which CD8 T cells that acquire constitutive persistent IL-15Rα expression are at a selective advantage and become founder cells, outgrow other lymphocytes, and lead to the establishment of a leukemia-like condition.

scholarly journals Selective anergy of V beta 8+ T cells in human immunodeficiency virus-infected individuals.

1994 ◽  
Vol 179 (2) ◽  
pp. 413-424 ◽  
Author(s):  
G Dadaglio ◽  
S Garcia ◽  
L Montagnier ◽  
M L Gougeon
Keyword(s):  
Human Immunodeficiency Virus ◽  
T Cells ◽  
T Cell ◽  
Hiv Infection ◽  
Cd8 T Cells ◽  
Clinical Status ◽  
Interleukin 2 ◽  
Cell Subset ◽  
T Cell Subset ◽  
Immunodeficiency Virus

We have analyzed the V beta usage by CD4+ and CD8+ T cells from human immunodeficiency virus (HIV)-infected individuals in response to an in vitro stimulation with the superantigenic erythrogenic toxin A (ETA) of Streptococcus pyogenes. ETA amplifies specifically CD4+ and CD8+ T cells from control donors expressing the V beta 8 and the V beta 12 elements. When peripheral T cells from asymptomatic HIV-infected individuals were stimulated with ETA, there was a complete lack of activation of the V beta 8+ T cell subset, whereas the V beta 12+ T cell subset responded normally to the superantigen. This V beta-specific anergy, which was also observed in response to staphylococcal enterotoxin E (SEE), affected both CD4+ and CD8+ T cells and represented an intrinsic functional defect rather than a specific lack of response to bacterial superantigens since it was also observed after a stimulation with V beta 8 monoclonal antibodies. The V beta 8 anergic T cells did not express interleukin 2 receptors (IL-2Rs) and failed to proliferate in response to exogenous IL-2 or IL-4, suggesting that this anergy was not a reversible process, at least by the use of these cytokines. The unresponsiveness of the V beta 8 T cell subset is frequent since it was found in 56% of the patients studied, and comparison of the clinical status of responder vs. anergic patients indicated that the only known common factor between them was HIV infection. In addition, it is noteworthy that the anergy of the V beta 8 subset may be a very early phenomenon since it was found in a patient at Centers for Disease Control stage I of the disease. These data provide evidence that a dominant superantigen may be involved in the course of HIV infection and that the contribution of HIV has to be considered.

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