scholarly journals Escape from suppression: tumor-specific effector cells outcompete regulatory T cells following stem-cell transplantation

Blood ◽  
2008 ◽  
Vol 111 (4) ◽  
pp. 2112-2121 ◽  
Author(s):  
Paria Mirmonsef ◽  
Gladys Tan ◽  
Gang Zhou ◽  
Tricia Morino ◽  
Kimberly Noonan ◽  
...  
Keyword(s):  
T Cells ◽  
Stem Cell ◽  
T Cell ◽  
Regulatory T Cells ◽  
Immune Reconstitution ◽  
Effector T Cells ◽  
Cell Transplant ◽  
Transplant Recipients ◽  
Tumor Bearing ◽  
Specific Effector

Immune reconstitution of autologous hematopoietic stem-cell transplant recipients with the progeny of mature T cells in the graft leads to profound changes in the emerging functional T-cell repertoire. In the steady state, the host is frequently tolerant to tumor antigens, reflecting dominant suppression of naive and effector T cells by regulatory T cells (Tregs). We examined the relative frequency and function of these 3 components within the tumor-specific T-cell compartment during immune reconstitution. Grafts from tumor-bearing donors exerted a significant antitumor effect in irradiated, syngeneic tumor-bearing recipients. This was associated with dramatic clonal expansion and interferon-γ (IFNγ) production by previously tolerant tumor-specific T cells. While donor-derived Tregs expanded in recipients, they did not inhibit the antigen-driven expansion of effector T cells in the early posttransplantation period. Indeed, the repopulation of tumor-specific effector T cells significantly exceeded that of Tregs, the expansion of which was limited by IL-2 availability. Although the intrinsic suppressive capacity of Tregs remained intact, their diminished frequency was insufficient to suppress effector cell function. These findings provide an explanation for the reversal of tolerance leading to tumor rejection in transplant recipients and likely contribute to the efficacy of adoptive T-cell therapies in lymphopenic hosts.

Escape from Suppression: Tumor-Specific Effector Cells Out-Compete Regulatory T Cells Following Stem Cell Transplantation.

Blood ◽  
2006 ◽  
Vol 108 (11) ◽  
pp. 69-69
Author(s):  
Paria Mirmonsef ◽  
Gladys Tan ◽  
Gang Zhou ◽  
Tricia Pyhel ◽  
Ivan M. Borrello ◽  
...  
Keyword(s):  
T Cells ◽  
Stem Cell ◽  
Tumor Antigen ◽  
Immune Reconstitution ◽  
Effector T Cells ◽  
Transplant Recipients ◽  
Tumor Bearing ◽  
Established Tumor ◽  
Specific Effector

Abstract Autologous hematopoietic stem cell (HSC) transplantation is an accepted therapy for many hematological malignancies. High dose chemo-radiation reduces tumor burden but also ablates lymphohematopoiesis. Subsequent infusion of cellular grafts containing HSC and mature lymphocytes “rescues” the host from this otherwise lethal ablation, and initiates immune reconstitution. In many systems, tumor-specific T cells are functionally tolerant in the presence of established tumor. Paradoxically, however, the infusion of these lymphocytes into irradiated tumor-bearing syngeneic recipients unmasks effector function manifested as prolonged progression-free survival when compared to recipients treated with lymphocytes from non-tumor bearing donors. We have recently demonstrated that this tolerant tumor-specific T cell population from mice with established tumor is in fact a heterogeneous mixture of naive, effector, and regulatory T cells (Tregs), which as a whole are rendered functionally unresponsive through dominant suppression. The apparent reversal of tolerance in the post-transplant setting prompted a more detailed examination of the fate of these individual components during immune reconstitution. Here, we show that CD4+ T cells specific for a model tumor antigen are hyporesponsive to antigen when isolated from mice harboring an established systemic B cell lymphoma. Upon transfer into irradiated lymphoma-bearing mice, however, these cells undergo robust antigen-driven clonal expansion, and their ability to produce interferon gamma (IFNγ) is restored. Notably, in spite of the presence of tumor in the transplant recipients, tolerance to tumor antigen was not established in the early post-transplant period, even for mice receiving naive T cells in the graft. Tumor-specific CD4+CD25+Foxp3+ Tregs isolated from the donors were found to undergo a modest tumor-antigen-driven expansion in transplant recipients. When isolated from recipients, such cells maintained expression of Foxp3 and their capacity to suppress naive T cells when cultured in vitro. However, the presence of tumor-specific Tregs failed to significantly inhibit the expansion of naive or effector T cells specific for tumor in vivo, when examined 2 weeks post BMT. Indeed, the expansion of tumor-specific effector T cells significantly exceeded the expansion of Tregs, resulting in a nearly five-fold increase in the effector:Treg ratio. At the ratios present during this phase of immune reconstitution, the frequency of Tregs was insufficient to suppress effector cell function (proliferation and IFNγ production) when studied in vitro. This accounts for the reversal of tolerance identified in the population as a whole and its capacity to mediate tumor rejection.

High Proportions of CD4+CD25hi T Cells Pretransplant Correlate with Worse Overall Survival after Stem Cell Transplant.

Blood ◽  
2006 ◽  
Vol 108 (11) ◽  
pp. 3126-3126
Author(s):  
Adria Prieto-Hinojosa ◽  
J. Alejandro Madrigal ◽  
Bronwen E. Shaw ◽  
Neema P. Mayor ◽  
Stephen G.E. Marsh ◽  
...  
Keyword(s):  
Overall Survival ◽  
T Cells ◽  
Stem Cell ◽  
T Cell ◽  
Regulatory T Cells ◽  
Regulatory T Cell ◽  
Regulatory Function ◽  
Cell Transplant ◽  
Mrna Levels ◽  
Foxp3 Mrna

Abstract Regulatory cells may have a modulatory effect on alloreactive phenomena following hematopoietic stem cell transplantation (HSCT), although their role in this setting in patients remains controversial. We have analysed the effect of pre-conditioning peripheral blood levels of T-regs on the outcome of 89 adult patients undergoing HLA-identical (10/10) unrelated donor (UD)-HSCT. Allografts were T-cell depleted with Alemtuzumab, which has been described to spare T-regs from, and we found that higher proportion of CD4+CD25hi T-cells correlated with worse survival (p=0.002). This higher proportion also correlated with higher incidence of relapse (p=0.0274) and with higher incidence of chronic (c) GvHD (p=0.033) but not with the incidence of aGvHD. Regulatory T cells (T-regs) are a naturally occurring regulatory population of CD4+CD25hi T-cells known to express the transcription repressor FoxP3 and to produce anti-inflammatory cytokines such as TGFβ and may therefore affect patient survival. We analyse the profile of the CD4+CD25hiT cells in our cohort. In our healthy donor control group (n=30), CD4+CD25hi-expression associated with both, FoxP3 mRNA-levels (r=0.649; p=0.001) and TGFβ production (r=0.912; p<0.001), as previously described for T-regs. In preconditioning patient samples however, CD4+CD25hi-expression had a strong correlation with TGFβ regulatory cytokine production (r=0.863; p<0.001) as expected. However, FoxP3 mRNA-expression correlated neither with the CD4+CD25hi T-regs phenotype (r=0.280; p=0.040), nor with the production of TGFβ (r=0.229; p=0.156), and appeared not be an accurate marker for regulatory T-cell function in this patient setting. In addition, an inverse correlation with TNFα expression (r=−0.458 p<0.001) was found that may argue that the CD4+CD25hi cells represent a true regulatory population and not activated cells. This suggests either that activated cells that are not expressing FOXP3 might be included in the CD4+CD25hi population or that CD4+CD25loFOXP3+ cells have not acquire the regulatory function (i.e. they are not expressing TGFβ). In summary, CD4+CD25hi Regulatory T cells may have an impact suppressing allo-responses against the tumour, decreasing the overall survival by increasing the rates of relapse. Although, in mice CD4+CD25hi population have been clearly identified by the expression of the FOXP3, which encodes a transcription repressor, in humans this remains controversial, where FOXP3 expression is not exclusive of the CD4+CD25hi population. Relying on the expression of CD4+CD25hi and FOXP3 in patients is insufficient to determine regulatory T cell numbers and suggests that other parameters of regulatory function should be taken in to account.

CD4+CD25+ Regulatory T Cells Enhance Immune Reconstitution Following Allogeneic Hematopoietic Cell Transplantation by Protecting Thymic and Lymphoid Compartments from Graft-Versus-Host Disease Damage without Impacting T Cell Repertoire Development.

Blood ◽  
2006 ◽  
Vol 108 (11) ◽  
pp. 70-70 ◽  
Author(s):  
Vu H. Nguyen ◽  
Daisy Chang ◽  
Sumana Shashidhar ◽  
Michael Bachmann ◽  
Christopher H. Contag ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Regulatory T Cells ◽  
Graft Versus Host Disease ◽  
Immune Reconstitution ◽  
Hematopoietic Cell Transplantation ◽  
Effector T Cells ◽  
T Cell Repertoire ◽  
Cell Repertoire ◽  
Graft Versus Host

Abstract Regulatory T cells (Treg) protect from acute graft-versus-host disease (GvHD) in murine models of major-MHC mismatched hematopoietic cell transplantation (HCT) presumably by dampening the proliferation of mature effector T cells. It is unclear whether the effect of Treg on effector T cells is a selective or nonselective process or if Treg regulate the process of intrathymic and peripheral T cell maturation and selection following HCT, particularly given the intrinsic link of GvHD and immune reconstitution. We previously showed that Treg improved the quantitative and functional lymphoid reconstitution in a murine model of HCT. In the current study, we hypothesize that Treg prevent thymic and lymphoid damage from GvHD, leading to enhanced lymphoid reconstitution. Lethally-irradiated adult thymectomized Balb/c (H2d) recipients were transplanted with wild-type FVB (H2q) T cell depleted bone marrow (TCD-BM) cells and CD4+/CD8+ cells (Tcon), the latter to induce GvHD, with or without donor Treg given at a 1:1 dose ratio with Tcon. At day 30, when all groups had reached full donor chimerism, transplant recipients were challenged with murine CMV (5×105 pfu/mouse) intraperitoneally. At day 90, survival for thymectomized groups with TCD-BM alone, with Tcon, or with Tcon+Treg was 78%, 0%, and 45%, respectively, compared to 100%, 0%, and 86% survival in their respective euthymic infected counterparts (p&lt;0.05 for thymectomized vs euthymic Treg groups). Elispot for Interferon-γ showed CMV-specific donor responses in all infected groups. CMV viral titers in the liver and kidney 2 weeks after infection was lower in recipients that received Treg compared to animals that received Tcon alone. Compared to euthymic transplant controls, thymectomized animals had higher viral titers in the liver, lungs, and kidneys in all groups. Uninfected thymectomized mice in the respective groups served as controls to separate the effect of CMV infection and GvHD on survival. All animals, infected or uninfected, that received Treg had no evidence of clinical GvHD while animals that received Tcon alone had significant GvHD. In euthymic recipients, gross and histologic examination confirmed the general preservation of thymic integrity and architecture in animals that received Treg compared with smaller involuted thymuses partially replaced by adipose tissue in animals that received Tcon alone. T cell repertoire assessed by V-beta TCR screening with FACS analysis showed a polyclonal distribution in animals with or without Treg. Spectratyping at day 30 post-transplantation showed that Treg had no significant impact on the TCR repertoire diversity in animals which received Tcon. Based on survival of a subset of infected thymectomized animals that received Treg, we evaluated the impact of Treg on secondary lymphoid organs following HCT. Animals without transferred Treg had significant splenic and lymph node fibrosis and hypoplasia with a reduction in T cell numbers due to GvHD. Our findings indicate that Treg indirectly enhance immune reconstitution by protecting the thymic and secondary lymphoid compartments from GvHD damage, allowing the generation and peripheral expansion of lymphoid cells without impacting the diversity of T cell repertoire.

Prospective simultaneous quantification of human cytomegalovirus-specific CD4+ and CD8+ T-cell reconstitution in young recipients of allogeneic hematopoietic stem cell transplants

Blood ◽  
2006 ◽  
Vol 108 (4) ◽  
pp. 1406-1412 ◽  
Author(s):  
Daniele Lilleri ◽  
Giuseppe Gerna ◽  
Chiara Fornara ◽  
Laura Lozza ◽  
Rita Maccario ◽  
...  
Keyword(s):  
T Cells ◽  
Stem Cell ◽  
T Cell ◽  
Hematopoietic Stem Cell ◽  
Human Cytomegalovirus ◽  
Immune Reconstitution ◽  
Hcmv Infection ◽  
Cd8 T Cell ◽  
Cell Transplant ◽  
Hematopoietic Stem

AbstractWe investigated immune reconstitution against human cytomegalovirus (HCMV) in 57 hematopoietic stem cell transplant (HSCT) recipients, aged 1 to 24 years, through a novel method combining T-cell stimulation by HCMV-infected autologous dendritic cells with simultaneous cytometric quantification of HCMV-specific, IFNγ-producing CD4+ and CD8+ T cells. Lymphoproliferative response (LPR) to HCMV antigens was also determined. Patients were stratified into 2 groups according to HCMV serostatus, comprising 39 HCMV-seropositive (R+) and 18 HCMV-seronegative (R–) patients who received a transplant from a sero-positive donor. Recovery of both HCMV-specific CD4+ and CD8+ T-cell immunity occurred in all 39 R+ patients within 6 months and in 6 (33%) of 18 R– patients within 12 months. In R+ patients, the median numbers of HCMV-specific CD8+ and CD4+T cells were significantly higher than those of healthy controls, starting from days +60 and +180, respectively. In R– patients, the median numbers of HCMV-specific T cells were consistently lower than in R+ patients. LPR was delayed compared with reconstitution of IFNγ-producing T cells. Patients with delayed specific immune reconstitution experienced recurrent episodes of HCMV infection. HCMV seropositivity of young HSCT recipients is the major factor responsible for HCMV-specific immune reconstitution, irrespective of donor serostatus, and measurement of HCMV-specific T cells appears useful for correct management of HCMV infection.

Enhanced Immune Reconstitution and Function by CD4+CD25+ Regulatory T Cells Following Allogeneic Hematopoietic Cell Transplantation.

Blood ◽  
2005 ◽  
Vol 106 (11) ◽  
pp. 64-64
Author(s):  
Vu H. Nguyen ◽  
Sumana Shashidhar ◽  
Robert Zeiser ◽  
Lena Ho ◽  
Janice M.Y. Brown ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Regulatory T Cells ◽  
Cell Transplantation ◽  
Immune Reconstitution ◽  
Hematopoietic Cell Transplantation ◽  
Effector T Cells ◽  
P Value ◽  
Post Transplantation ◽  
Time Points

Abstract Regulatory T cells (Treg), defined phenotypically by CD4+CD25+ expression, reduce the incidence and severity of acute graft-versus-host disease (GvHD) in murine models of major-MHC mismatched hematopoietic cell transplantation (HCT), presumably by dampening the proliferation and activation of mature effector T cells. It is unclear whether the effect of Treg on effector T cells is a selective or nonselective process or if Treg regulate the process of intrathymic and peripheral T cell maturation and selection following HCT, particularly given the intrinsic link of GvHD and immune reconstitution. The current study assessed the impact of Treg on the quantitative and functional lymphoid reconstitution in a murine model of major-MHC mismatched HCT. Treg (5x105) from the spleen and lymph nodes of FVB/N (H2q) mice were co-transplanted into lethally irradiated Balb/c (H2d) host along with wild-type FVB/N T-cell depleted bone marrow (TCD-BM) cells (5x106) and splenocytes (1.25x106) (Tcon), the latter to induce GvHD. Chimerism studies were performed on day 14 and 40 post-transplantation to measure the level of donor immune reconstitution. At both time points, total lymphoid reconstitution was delayed in the GvHD control group and enhanced in the recipients transplanted with Treg (p-values=0.0005 on day 14, &lt;0.0001 on day 40). T cell reconstitution, particularly CD4+ cells, was enhanced in the Treg group at both time points and reached statistical significance on day 40 (p-value=0.003). The number of donor natural killer cells was particularly enhanced on day 14 in the Treg recipients (p-value=0.0003). B-cell reconstitution, as measured by percentage of CD19+ cells, was minimal for all groups at day 14, but was enhanced at day 40 in recipient animals that received Treg (p-value=0.006). The T cell repertoire assessed by V-beta TCR screening with FACS analysis showed a polyclonal distribution. To determine if the improved and diverse lymphoid reconstitution is associated with increased immune function, mice were challenged with murine CMV (5x10e5 pfu/mouse) intraperitoneally at day 14 post-transplantation. Two weeks after infection, 66% of animals which received Treg in addition to Tcon, and 11% of animals which received Tcon alone were alive (p-value=0.05). Uninfected mice in the respective groups served as controls to separate the effect of CMV infection and GvHD on survival. Compared to infected animals, no deaths were observed in the respective uninfected groups at this time point (Tcon alone, p-value=0.0004; Treg+Tcon, p-value=0.21). In both infected and control uninfected animals, Treg treated animals had no evidence of significant clinical GvHD while animals that received Tcon alone had severe GvHD. These findings indicate that Treg enhance both the quantitative and functional recovery of the lymphoid cell populations while providing protection against GvHD.

scholarly journals Autologous stem cell transplantation aids autoimmune patients by functional renewal and TCR diversification of regulatory T cells

Blood ◽  
2016 ◽  
Vol 127 (1) ◽  
pp. 91-101 ◽  
Author(s):  
Eveline M. Delemarre ◽  
Theo van den Broek ◽  
Gerdien Mijnheer ◽  
Jenny Meerding ◽  
Ellen J. Wehrens ◽  
...  
Keyword(s):  
T Cells ◽  
Stem Cell ◽  
T Cell ◽  
Regulatory T Cells ◽  
Stem Cell Transplantation ◽  
Clinical Improvement ◽  
Autologous Stem Cell Transplantation ◽  
T Cell Reconstitution ◽  
Key Points ◽  
Autologous Hsct

Key Points Autologous HSCT induces functional renewal of regulatory T cells as well as a strong Treg TCR diversification in autoimmune patients. Adding regulatory T cells to the graft does not lead to additional clinical improvement but results in delayed donor T-cell reconstitution.

New Developments in Allotransplant Immunology

Hematology ◽  
2003 ◽  
Vol 2003 (1) ◽  
pp. 350-371 ◽  
Author(s):  
A. John Barrett ◽  
Katayoun Rezvani ◽  
Scott Solomon ◽  
Anne M. Dickinson ◽  
Xiao N. Wang ◽  
...  
Keyword(s):  
T Cells ◽  
Stem Cell ◽  
T Cell ◽  
Stem Cell Transplantation ◽  
Cell Transplantation ◽  
Immune Reconstitution ◽  
Cytokine Gene ◽  
Post Transplant ◽  
Cytokine Milieu ◽  
Cytokine Gene Polymorphisms

Abstract After allogeneic stem cell transplantation, the establishment of the donor’s immune system in an antigenically distinct recipient confers a therapeutic graft-versus-malignancy effect, but also causes graft-versus-host disease (GVHD) and protracted immune dysfunction. In the last decade, a molecular-level description of alloimmune interactions and the process of immune recovery leading to tolerance has emerged. Here, new developments in understanding alloresponses, genetic factors that modify them, and strategies to control immune reconstitution are described. In Section I, Dr. John Barrett and colleagues describe the cellular and molecular basis of the alloresponse and the mechanisms underlying the three major outcomes of engraftment, GVHD and the graft-versus-leukemia (GVL) effect. Increasing knowledge of leukemia-restricted antigens suggests ways to separate GVHD and GVL. Recent findings highlight a central role of hematopoietic-derived antigen-presenting cells in the initiation of GVHD and distinct properties of natural killer (NK) cell alloreactivity in engraftment and GVL that are of therapeutic importance. Finally, a detailed map of cellular immune recovery post-transplant is emerging which highlights the importance of post-thymic lymphocytes in determining outcome in the critical first few months following stem cell transplantation. Factors that modify immune reconstitution include immunosuppression, GVHD, the cytokine milieu and poorly-defined homeostatic mechanisms which encourage irregular T cell expansions driven by immunodominant T cell–antigen interactions. In Section II, Prof. Anne Dickinson and colleagues describe genetic polymorphisms outside the human leukocyte antigen (HLA) system that determine the nature of immune reconstitution after allogeneic stem cell transplantation (SCT) and thereby affect transplant outcomethrough GVHD, GVL, and transplant-related mortality. Polymorphisms in cytokine gene promotors and other less characterized genes affect the cytokine milieu of the recipient and the immune reactivity of the donor. Some cytokine gene polymorphisms are significantly associated with transplant outcome. Other non-HLA genes strongly affecting alloresponses code for minor histocompatibility antigens (mHA). Differences between donor and recipient mHA cause GVHD or GVL reactions or graft rejection. Both cytokine gene polymorphisms (CGP) and mHA differences resulting on donor-recipient incompatibilities can be jointly assessed in the skin explant assay as a functional way to select the most suitable donor or the best transplant approach for the recipient. In Section III, Dr. Nelson Chao describes non-pharmaceutical techniques to control immune reconstitution post-transplant. T cells stimulated by host alloantigens can be distinguished from resting T cells by the expression of a variety of activation markers (IL-2 receptor, FAS, CD69, CD71) and by an increased photosensitivity to rhodamine dyes. These differences form the basis for eliminating GVHD-reactive T cells in vitro while conserving GVL and anti-viral immunity. Other attempts to control immune reactions post-transplant include the insertion of suicide genes into the transplanted T cells for effective termination of GVHD reactions, the removal of CD62 ligand expressing cells, and the modulation of T cell reactivity by favoring Th2, Tc2 lymphocyte subset expansion. These technologies could eliminate GVHD while preserving T cell responses to leukemia and reactivating viruses.

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