Allogeneic marrow stromal cells are immune rejected by MHC class I– and class II–mismatched recipient mice

Abstract

It has been suggested that marrow stromal cells (MSCs) may be immunoprivileged and can engraft in allogeneic recipients with intact immune systems. We determined if the implantation of murine MSCs engineered to release erythropoietin (Epo) would be feasible in major histocompatibility complex (MHC)-mismatched allogeneic mice without immunosuppression, and we monitored hematocrit (Hct) as a reporter of MSC graft survival. MSCs from C57Bl/6 mice were engineered to release murine Epo (Epo ؉ MSCs) and implanted subcutaneously in either syngeneic C57Bl/6 mice or MHC-mismatched Balb/c mice. In syngeneic recipients, the Hct rapidly rose from baseline level and remained higher than .88 (88%) for more than 200 days. However, in MHCmismatched recipient Balb/c mice, the Hct rose transiently and rapidly declined to baseline values. Repeat implantations in these same mice were associated with an acquired refractoriness in the Hct response consistent with alloimmunization to donor Epo ؉ MSCs. Allogeneic MSC implants had an increased proportion of host-derived lymphoid CD8 ؉ , natural killer T (NKT), and NK infiltrating cells compared with syngeneic controls, and splenocytes isolated from Balb/c mice that had received implants also displayed a significant interferon-gamma (IFN␥) response to C57Bl/6 MSCs in vitro. These IntroductionBone marrow stromal cells (MSCs), 1 also sometimes referred to as mesenchymal stem cells, are promising for regenerative medicine due to their innate ability to differentiate into various cell types. [2][3][4][5] Thus, autologous MSCs and their genetically engineered progeny have potential use in several preclinical regenerative medicine scenarios, such as cardiovascular regeneration, 6-14 brain and spinal cord regeneration, 15,16 as well as bone and cartilage repair. [17][18][19][20][21][22][23] Furthermore, genetically engineered MSCs may operate as cellular vehicles for the delivery of therapeutic proteins in hereditary and acquired metabolic, endocrine, and malignant diseases. 4,[24][25][26][27][28][29][30] In vitro studies on human, baboon, and murine MSCs have revealed that MSCs are immunosuppressive. [31][32][33][34] Depending upon the experimental circumstances, suppression of mixed lymphocyte reaction (MLR) in vitro between major histocompatibility complex (MHC)-mismatched stimulator and responder cells by MSCs appears to arise from both contact-dependent 35 and soluble factors including, but not limited to, [36][37][38] hepatocyte growth factor (HGF) and transforming growth factor ␤1 (TGF-␤1). 32 However, alternative experimental settings suggest that MSCs may also behave as nonprofessional antigen-presenting cells (APCs). 39,40 In support of their in vivo immunosuppressive features are the observations that allogeneic MSCs may prolong skin allograft survival in immunocompetent baboons, 31 prevent the rejection of allogeneic B16 mouse melanoma cells in immunocompetent C3H mice, 34 and attenuate graft-versus-host disease in mice and humans. 38,41 The sum of these observations supports the...

How stem cells speak with host immune cells in inflammatory brain diseases

“…Allogeneic rodent MSCs are recognized by the host immune system in vivo, elicit a cellular and humoural immune response, and fail to induce tolerance in graft-versus-host disease (GVHD) (Badillo et al, 2008;Ringden and Le Blanc, 2011). When studied within a non-myeloablative allogeneic bone marrow (BM) transplantation setting in naive immune competent mice, infused allogeneic MSCs prime host T cells and induce a memory T-cell response, resulting in rejection of the BM graft (Eliopoulos et al, 2005;Nauta et al, 2006). This partial lack of immune competence has been attributed to defects in the expression of different components of antigen processing machinery by MSCs (e.g.…”

Immunoregulatory function of mesenchymal stem cells

“…infusion of allogeneic MSC in humans has led to encouraging results in different human diseases including GVHD [15], breast cancer [71], osteogenesis imperfecta [72], metachromatic leukodystrophy and Hurler syndrome [73], hematological malignancies [74] and stroke [75]. However, recent in vivo experiments raised some doubts about the reported immunoprivilege of MSC, indicating that at least in some cases, administration of allogeneic MSC into an MHC-mismatched host may result in their rejection [19]. Similarly, infusion of allogeneic MSC in mice receiving an allogeneic BM transplantation did not prevent BM rejection as efficiently as in mice infused with autologous MSC [18].…”

“…Since these early reports, many studies have demonstrated that MSC affect the function of different immunocompetent cell types, lending support to their pioneering utilization in acute graft-versus-host disease (GVHD) [15] and providing the rationale for their possible use in the treatment of autoimmune disorders [16]. However, recent reports have stressed that the outcome of the interaction between MSC and immune cells is strongly influenced by environmental factors, possibly leading to conflicting results [17][18][19]. This review addresses the known effect of MSC on the immune system in light of their possible use in the treatment of immune-mediated diseases.…”

Nonviral gene delivery of erythropoietin by mesenchymal stromal cells

“…31 After a rapid increase in hematocrit, the values returned to normal within 5 weeks after syngeneic transplantation. Allogeneic MSCs induced the formation of neutralizing anti-EPO antibodies with secondary anemia.…”

“…21 Whereas the mechanisms leading to autoimmune responses are still unclear, there was no evidence that the EPO secreted by MSCs was the cause of the immune response. 31 Therefore, we hypothesized that the production of anti-EPO antibodies in the host might be associated with changes induced by the viral transduction of MSCs. However, our results refute this hypothesis, as nucleofected EPO-secreting MSCs also induced the production of antibodies against EPO and the second transgene, GFP, in immunocompetent mice.…”