Bone marrow graft-versus-host disease: early destruction of hematopoietic niche after MHC-mismatched hematopoietic stem cell transplantation

Abstract

Disrupted hematopoiesis and delayed immune reconstitution are life-threatening complications of allogeneic hematopoietic stem cell transplantation (allo-HSCT). Although graft-versus-host disease (GVHD) is a major risk factor for the bone marrow (BM) insufficiency, how GVHD impairs BM hematopoiesis has been largely unknown. We hypothesized that BM stromal niche could be a target of GVHD. In major histocompatibility complex (

T-cell reconstitution after allogeneic stem cell transplantation: assessment by measurement of the sjTREC/ TREC ratio and thymic naive T cells

“…26 This pattern suggests a block of T-cell neogenesis at a very early stage of development, i.e., the stage of the early thymic progenitors 9,25 or possibly even the thymus-seeding progenitors in the peripheral blood or bone marrow. 37,38 There is good experimental evidence that acute GvHD results in early damage of the bone marrow stromal niches and a subsequent loss of early lymphoid progenitors. 38 There is also growing evidence from mouse models of hematopoietic cell transplantation that the availability of thymus-seeding progenitors could be the rate-limiting factor for T-cell neogenesis, independently of allogeneic effects.…”

Allogeneic T cells impair engraftment and hematopoiesis after stem cell transplantation

“…It has been shown that cytokines, such as IL-6, TGFβ, TNFα, and IFNγ, suppress hematopoiesis by blocking lineage commitment (29), impairing cell division (30), and inducing programmed cell death (31). Inflammation can also damage the host cellular components of HSC niches (13), making the marrow inhospitable for blood cell production. Thus, the way that donor lymphocytes exert negative effects on hematopoiesis likely involves both direct and indirect perturbation of HSC function, survival, and engraftment.…”

“…The body of data demonstrating the deleterious effects of GVHR on BM and lymphoid function (13)(14)(15)(16)(17)(18)(19)(20)(26)(27)(28) is often overlooked or underestimated. We previously reported that even low amounts of T cells cause subclinical, yet lympho-depleting, GVHR (25).…”

“…Although there are serious concerns that TCD results in significantly increased infectious complications, GVHD itself is known to impair immune function post-HCT (3)(4)(5)13). GVHD-associated lymphoid hypoplasia has been well described (6-8, 14-17).…”

“…Myelosuppression, the most telling manifestation of graft-versus-host reactions (GVHR) directed against hematopoietic elements has also been reported. It appears that the hematopoietic system is the most sensitive target of donor immunity, as relatively low numbers of T cells that do not damage other target organs can nonetheless induce marrow aplasia (13,(18)(19)(20). Given the important consequences that attack of the BM and lymphoid organs have on the outcomes of clinical allogeneic HCT, surprisingly little is known about GVHR as it pertains to hematopoiesis and the establishment of donor chimerism.…”