T-cell receptor repertoire usage after allografting differs between CD4+CD25+ regulatory T cells and their CD4+CD25  counterpart

Fozza, Claudio; Nadal, E.; Longinotti, M; Dazzi, Francesco

doi:10.3324/haematol.10774

Cited by 13 publications

(4 citation statements)

References 48 publications

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“…A significant correlation was demonstrated between increased number of CD4 + Treg and several markers of disease aggressiveness, such as bone marrow blast infiltration >5%, high International Prognostic Scoring System (IPSS) score and disease progression, while none of these correlations was significant for CD8 + Treg (25). This study also confirmed that Treg display a polyclonal CDR3 profile, as already observed in the postallograft setting (26). In addition, most Treg were shown to belong to the naive subset, especially in high‐risk patients (25).…”

Section: The Role Of Specific Cell Types In Mdssupporting

confidence: 89%

Are T‐cell dysfunctions the other side of the moon in the pathogenesis of myelodysplastic syndromes?

Fozza

Longinotti

2012

European J of Haematology

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Myelodysplastic syndromes (MDS), a heterogeneous group of clonal disorders arising from a primitive CD34 + myeloid-oriented stem cell, are characterised by an inefficient maturation of haematopoietic precursors as well as by an increased risk of evolution towards acute myeloid leukaemia (AML). A series of recurrent molecular, cytogenetic and epigenetic alterations presenting with variable frequency can be found in about 50% of MDS patients [reviewed in Ref. (1)]. Moreover, ongoing investigations by next generation sequencing as well as by genome wide array analyses have been adding further complexity to the molecular pathogenesis of MDS. In fact, a large number of MDS patients with otherwise normal karyotype show cryptic DNA lesions in their somatic peripheral blood cells when investigated by such modern techniques (2). On the whole, such an increasing amount of MDS-associated DNA defects clearly indicate that a genetic and ⁄ or epigenetic deregulation of CD34 + haematopoietic stem cell growth and differentiation plays a major role in the MDS pathogenesis. On the other hand, two clinical observations strongly suggest that an abnormal immune response might also play a role in both bone marrow insufficiency and disease progression.Firstly, in 1997, Molldrem and colleagues described a subgroup of MDS patients which responded to immunosuppressive treatment with antithymocyte globulin (ATG) (3). More recently, patients affected by aplastic anaemia (AA) have been demonstrated to potentially evolve to a typical MDS showing trisomy 8 or monosomy 7 (4). These basic observations encouraged several laboratories all over the world to investigate the occurrence of immunocompetence defects in MDS. This review describes the advances in the understanding of the subtle cellular immune response dysfunctions which can be detected in MDS patients when their circulating or bone marrow T-cells are evaluated by phenotypic or genotypic analyses. Immune manifestations in MDS: incidence, risk and clinical featuresSince when in 1996 Hamblin and colleagues highlighted two cases of autoimmune haemolytic anaemia among 104 patients with MDS (5), several studies have reported that the incidence of immune manifestations ranges around 10-15% in the overall MDS population (6-8). AbstractEven though the pathogenesis of myelodysplastic syndromes (MDS) is dominated by an inefficient maturation of haematopoietic precursors, also immune mechanisms seem to play a crucial functional role. In this review, we will first describe the clinical and laboratory autoimmune manifestations often detectable in MDS patients. We will then focus on studies addressing the mechanisms of T-cell activation and their implications in the disease history. The potential impact of specific cell subsets, such as regulatory T-cells, Th17 cells and natural killer cells, will be also described. We will finally focus on potential therapeutic approaches based on immunomodulation, ranging from more classical immunosuppressive drugs to vaccination and transplantation strategies.

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Section: The Role Of Specific Cell Types In Mdssupporting

confidence: 89%

Are T‐cell dysfunctions the other side of the moon in the pathogenesis of myelodysplastic syndromes?

Fozza

Longinotti

2012

European J of Haematology

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“…Furthermore, these data rule out the possibility that a change in the repertoire of the conventional T cell pool of the recipient as a result of the homeostatic expansion (36) is the main factor responsible for a reduction or deletion in the number of HYspecific T cell precursors. As a confirmation of this, we have recently observed that in patients after HSCT, the TCR repertoire of T regs , as analyzed by spectratyping, is much more diverse as compared with the frequent oligoclonalities detected in conventional CD4 ϩ cells from the same patients (37).…”

Section: Subsequently Infused Hemopoietic Cells (R Laylor Et Al Pementioning

confidence: 58%

Low-intensity transplant regimens facilitate recruitment of donor-specific regulatory T cells that promote hematopoietic engraftment

Weng

Dyson

Dazzi

2007

Proc. Natl. Acad. Sci. U.S.A.

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Low-or reduced-intensity conditioning regimens for allogeneic hemopoietic stem cell transplantation are effective at establishing donor hematopoietic engraftment and host-vs.-graft (HvG) tolerance. We investigated the mechanisms of HvG tolerance induction and maintenance in an animal model in which transplantation of sublethally irradiated female recipients with bone marrow (BM) from syngeneic male donors produces mixed chimerism. Splenocytes from chimeric mice inhibited HY-specific CD8 ؉ T cell responses both in vitro and in vivo, and their adoptive transfer facilitated donor hematopoietic engraftment. These properties were contained within the CD4 ؉ CD25 ؉ population. The conditioning protocol alone led to a proportional expansion of regulatory T cells (T regs), but the inhibitory activity was induced only if male BM was infused. The administration of anti-CD25-depleting antibodies to conditioned recipients at time of BM transplantation prevented donor-recipient chimerism but did not affect engraftment if performed after the establishment of chimerism, thus indicating that recipient Tregs are required for the generation but not the maintenance of HvG tolerance. We conclude that donor-specific Tregs of recipient origin are recruited when the donor antigens are present during reduced-intensity conditioning-induced Treg expansion.host vs. graft ͉ reduced-intensity conditioning ͉ stem cell transplantation ͉ tolerance A llogeneic hemopoietic stem cell transplantation (HSCT) is a well established treatment modality for malignant and nonmalignant diseases (1). The conventional approach to condition the patient with fully myeloablative regimens has recently been reconsidered in light of the therapeutic goals (2) and led to the development of low-or reduced-intensity conditioning (RIC) regimens whereby the role of conditioning is confined to the establishment of mixed hemopoietic chimerism and the consequent host-vs.-graft (HvG) tolerance (3, 4). Evidence exists that such approaches could also be used before solid organ transplantation (5) and to prevent the rejection of genetically modified cells (6).The coexistence of donor and recipient hematopoiesis after RIC regimens creates durable HvG tolerance with no need for long-term immunosuppression. Despite the importance of central and peripheral deletional tolerance in the establishment of mixed chimerism (7), active regulation has emerged as being central (8,9). Natural regulatory T (T reg ) cells are a subpopulation of thymus-derived CD4 ϩ T cells that constitutively express CD25 (10, 11) and the forkhead box P3 (FoxP3) gene product (12). They play a crucial role in peripheral tolerance, susceptibility to autoimmune disease (13), and tumor immunity (14), as well as in the induction of transplantation tolerance (15-18).Very little is known about the role of T regs in allogeneic HSCT and to what extent they are affected by immune reconstitution (19) but, in animal models, their adoptive transfer controls graft-vs.-host disease (GvHD) (20-24) and induce specific toleranc...

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“…For example, Treg clones with higher avidity for minor histocompatibility alloantigens are more likely to preferentially expand and then undergo apoptosis under the conditions of immune reconstitution found in our patients. This process may further skew the diversity of the Treg TCR repertoire by selectively depleting those Tregs that are capable of suppressing alloimmune responses in vivo (60,61). Second, previous studies have shown that the expression of tissue homing receptors on Treg changes during the conversion from naive to activated/memory phenotype (62).…”

Section: Discussionmentioning

confidence: 99%

Altered regulatory T cell homeostasis in patients with CD4+ lymphopenia following allogeneic hematopoietic stem cell transplantation

Matsuoka¹,

Kim²,

McDonough³

et al. 2010

J. Clin. Invest.

214

211

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CD4 + CD25 + Foxp3 + Tregs have an indispensable role in the maintenance of tolerance after allogeneic HSC transplantation (HSCT). Patients with chronic graft-versus-host disease (GVHD) have fewer circulating Tregs, but the mechanisms that lead to this deficiency of Tregs after HSCT are not known. Here, we analyzed reconstitution of Tregs and conventional CD4 + T cells (Tcons) in patients who underwent allogeneic HSCT after myeloablative conditioning. Following transplant, thymic generation of naive Tregs was markedly impaired, and reconstituting Tregs had a predominantly activated/memory phenotype. In response to CD4 + lymphopenia after HSCT, Tregs underwent higher levels of proliferation than Tcons, but Tregs undergoing homeostatic proliferation also showed increased susceptibility to Fas-mediated apoptosis. Prospective monitoring of CD4 + T cell subsets revealed that Tregs rapidly expanded and achieved normal levels by 9 months after HSCT, but Treg levels subsequently declined in patients with prolonged CD4 + lymphopenia. This resulted in a relative deficiency of Tregs, which was associated with a high incidence of extensive chronic GVHD. These studies indicate that CD4 + lymphopenia is a critical factor in Treg homeostasis and that prolonged imbalance of Treg homeostasis after HSCT can result in loss of tolerance and significant clinical disease manifestations.

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T-cell receptor repertoire usage after allografting differs between CD4+CD25+ regulatory T cells and their CD4+CD25 counterpart

Cited by 13 publications

References 48 publications

Are T‐cell dysfunctions the other side of the moon in the pathogenesis of myelodysplastic syndromes?

Are T‐cell dysfunctions the other side of the moon in the pathogenesis of myelodysplastic syndromes?

Low-intensity transplant regimens facilitate recruitment of donor-specific regulatory T cells that promote hematopoietic engraftment

Altered regulatory T cell homeostasis in patients with CD4+ lymphopenia following allogeneic hematopoietic stem cell transplantation

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