Human mesenchymal stem cells isolated from bone marrow and lymphoid organs support tumor B-cell growth: role of stromal cells in follicular lymphoma pathogenesis

Amé-Thomas, Patricia; Hajjami, Hélène Maby–El; Monvoisin, Céline; Rémy, Jean; Monnier, Delphine; Caulet‐Maugendre, Sylvie; Guillaudeux, Thierry; Lamy, Thierry; Fest, Thierry; Tarte, Karin

doi:10.1182/blood-2006-05-020800

Cited by 212 publications

(177 citation statements)

References 65 publications

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“…In addition, we also found very low levels of donor-specific alloantibodies in all of the long-term surviving recipients. This attenuation of the humoral response may be a result of bone graft MSC-mediated down-regulation of T celldependent Ab production or be due to a direct inhibitory effect of MSCs on B cell function (55,56).…”

Section: Discussionmentioning

confidence: 99%

Free Bone Graft Attenuates Acute Rejection and in Combination with Cyclosporin A Leads to Indefinite Cardiac Allograft Survival

Wang

Ge²,

Arp³

et al. 2009

The Journal of Immunology

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We report on a novel approach aimed at preventing acute vascular rejection (AVR), one of the major unresolved hurdles of clinical transplantation. In a C3H-to-BALB/c heterotopic heart transplant model, we demonstrate that free bone transplantation combined with cyclosporin A suppresses antidonor Ab responses, induces indefinite cardiac allograft survival (>100 days), and preserves graft architecture. In contrast, untreated- or cyclosporin A alone-treated recipients rejected their cardiac grafts on days 7.7 ± 0.6 and 15.5 ± 1.1, respectively, with graft histology indicative of AVR. Splenic dendritic cells from nonrejecting recipients expressed low levels of MHC II, CD40, and CD86, reduced ability to stimulate donor cell proliferation, and augmented IL-10 production of responding T cells in vitro. Adoptive transfer of dendritic cells from long-term surviving recipients 1 day before cardiac grafting was able to confer hyporesponsiveness to naive BALB/c recipients of cardiac allografts. To determine whether graft survival was associated with hematopoietic or stromal elements of the transplanted free bone, we administered isolated bone marrow mononuclear cells or free bone that was irradiated to deplete hematopoietic elements. Although bone marrow mononuclear cells had no effect on cardiac graft survival, irradiated free bone transplantation was capable of prolonging graft survival. Most interestingly, the prolongation effect was Ag nonspecific, because third party irradiated bone graft was also effective. Due to the fact that current immunosuppressive approaches are clinically ineffective at preventing AVR, this study provides promise for further investigations of BM components as a means of addressing a currently unmet medical need.

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Section: Discussionmentioning

confidence: 99%

Free Bone Graft Attenuates Acute Rejection and in Combination with Cyclosporin A Leads to Indefinite Cardiac Allograft Survival

Wang

Ge²,

Arp³

et al. 2009

The Journal of Immunology

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“…Indeed a bone marrow-specific niche has already been proposed by several groups. [18][19][20] In consequence it could even be that clonally related and bone marrow-resident FLLC, instead of fully malignant FL cells, cause a relapse of lymphoma ( Figure 1E). …”

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confidence: 99%

Origin and migration of follicular lymphoma cells

Kluin

2013

Haematologica

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F ollicular lymphoma (FL) was described for the first time by Brill and Symmers in 1925. The primary cytogenetic lesion, the t(14;18) was identified in 1982, and the breakpoint at BCL2 in 1985. Based on observations that the t(14;18) originates from an erroneous recombination event in precursor B cells, 1 a model evolved in which the tumor develops linearly from such a precursor cell ( Figure 1A). Other cytogenetic events frequently accompany the t(14;18), and various authors have attempted to distinguish different subgroups of FL with differences in biological behavior, risk of transformation to an aggressive lymphoma, prognosis and overall survival on the basis of these additional events.2,3 Apart from these cytogenetic abnormalities not further discussed here, it is evident that FL represents a germinal center lymphoma with high expression of activation-induced deaminase (AID) and in consequence a pattern of ongoing somatic hypermutations of immunoglobulin (IG) loci. 4,5 This is not necessarily a continuous process since tumor cells may leave and (re)enter a germinal center and, in consequence, may periodically acquire novel somatic hypermutations of the IG genes. Indeed, by analysis of individual tumor cells or by molecular cloning of IGH rearrangements from a pool of tumor cells, it became evident that within each individual lymphoma not all tumor cells share the same somatic hypermutations. This implies subclonal evolution of the lymphoma, each clone being detectable by a unique fingerprint. Thus sampling of multiple (subsequent) lymph nodes of a FL patient might show different fingerprints of these mutations and this type of analysis may provide us with a "genealogical tree" of the individual lymphoma ( Figure 1B).The prototypic FL is a histologically low grade (grade 1 or 2) and clinically indolent lymphoma and affected patients have a median overall survival of approximately 7 years or longer. Of note the great majority of patients present with disseminated disease at the time of diagnosis implying an equally long or even longer period of subclinical disease. This is in line with the observations that approximately half of all healthy adult individuals harbor one or more B-cell clones with a t(14;18), only very few of these clones developing into clinically relevant disease. At present these cells are called "follicular lymphoma-like cells" or FLLC. [6][7][8] In fact occasional cells carrying these t(14;18) can already be identified in hyperplastic tonsils from children.9 Besides, so-called follicular lymphoma in situ (FLIS) lesions can be identified in less than 3% of all reactive lymph nodes. 10 In these lymph nodes, some germinal centers are focally involved by FL cells as detected by immunohistochemistry, polymerase chain reaction analysis and in situ hybridization for the t(14;18).Interestingly and in contrast to what was expected, these FLLC and likely also FLIS lesions represent expansions of lowaffinity IgM(D) expressing (post-germinal) memory B cells that have accumulated high loads of somatic ...

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“…CCL21 and CXCL12 immunostaining did not reveal significant differences in their expression between the two groups. These chemokines are likely to be synthesized by stromal cells, particularly fibroblastic reticular cells in the T cell zone as previously described and then to migrate to HEV/LV (36)(37)(38). Fibroblastic reticular cell networks are phenotypically and probably functionally altered during FL development, eventually contributing to immune suppression (38).…”

Section: Discussionmentioning

confidence: 99%

γδ T Lymphocytes Count Is Normal and Expandable in Peripheral Blood of Patients with Follicular Lymphoma, Whereas It Is Decreased in Tumor Lymph Nodes Compared with Inflammatory Lymph Nodes

Braza

Caraux

Rousset

et al. 2009

The Journal of Immunology

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γδ T lymphocytes are attractive effector cells for immunotherapy. In vitro, they can be expanded and kill efficiently a variety of tumor cells. The frequency and distribution of γδ T lymphocytes were compared in tumor lymph nodes of 51 patients with follicular lymphoma lymph nodes (FL-LNs) and 28 patients with inflammatory lymph nodes (I-LNs). γδ and CD8 T lymphocytes were less abundant in FL-LNs than in I-LNs (p ≤ 10−7). These lymphocytes were localized in the perifollicular zone outside of the tumor follicles. Perifollicular γδ T lymphocytes expressed CCR7, in contrast to peripheral blood γδ T lymphocytes and both perifollicular and peripheral blood γδ T lymphocytes expressed CXCR4. The very low number of perifollicular γδ T lymphocytes in FL-LNs could be explained in part by migratory problems because of absence of CCL19 expression in FL-LNs compared with I-LNs. Conversely, CCL21 and CXCL12 were similarly expressed in both FL-LNs and I-LNs. CCL19 and CCL21 were expressed in high endothelial venules and lymphatic vessels, whereas CXCL12 was expressed by stromal cells surrounding high endothelial venules and lymphatic vessels. Peripheral γδ T lymphocytes from 34 patients with FL, expanded with Phosphostim and IL-2 in vitro, had the same expansion capacity as those from healthy individuals. Thus, γδ T lymphocytes can be an attractive source for adoptive immunotherapy in patients with FL, providing they may home in tumor LNs.

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Human mesenchymal stem cells isolated from bone marrow and lymphoid organs support tumor B-cell growth: role of stromal cells in follicular lymphoma pathogenesis

Cited by 212 publications

References 65 publications

Free Bone Graft Attenuates Acute Rejection and in Combination with Cyclosporin A Leads to Indefinite Cardiac Allograft Survival

Free Bone Graft Attenuates Acute Rejection and in Combination with Cyclosporin A Leads to Indefinite Cardiac Allograft Survival

Origin and migration of follicular lymphoma cells

γδ T Lymphocytes Count Is Normal and Expandable in Peripheral Blood of Patients with Follicular Lymphoma, Whereas It Is Decreased in Tumor Lymph Nodes Compared with Inflammatory Lymph Nodes

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