Page 1759 - Hematology_ Basic Principles and Practice ( PDFDrive )

Chapter 99 Mesenchymal Stromal Cells 1563

production in mouse MSCs abolishes their ability to suppress T-cell two broad categories: prevention and treatment of GVHD, and
proliferation, a phenomenon not observed in human MSCs. In addi- adjuvant to HSC engraftment. Much has been done since the first
tion to IDO, other human-specific tolerance molecules such as described successful treatment of a 9-year-old boy suffering from
HLA-G are upregulated by IFN-γ in human MSCs but not in the acute steroid-resistant GVHD with MSCs. Several phase I/II clinical
murine system. These important differences between the mechanisms and multiinstitutional trials have been published with encouraging
of priming and action of immunosuppression by mouse versus results in adult or pediatric patients. In most studies, MSCs were
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human MSCs highlight some of the limitations of in vivo studies infused intravenously at a dose of 1–8 ×10 MSCs/kg in subjects with
assessing the immunosuppressive mechanism of action properties of GVHD. The intravenous route allowed the injection of several doses
murine MSCs in animal models of disease. of MSCs, and the number of MSC infusions was often increased in
patients with partial responses. MSCs were from HLA-identical
MESENCHYMAL STROMAL CELL IMMUNE PRIVILEGE: siblings or HLA-matched or -mismatched donors; however, the
response rate to MSC infusion was not related to the degree of HLA
A CONTROVERSIAL ISSUE matching. The largest academic, multicenter phase II experimental
study was described in 2008, in which 55 adult and pediatric patients
Based on the extensive results demonstrating the immunosuppressive with steroid-resistant acute GVHD were treated with steroids and
effect of MSCs in vitro, it was suggested that MSCs could use their MSC infusions. Thirty patients had a complete response, 53% of
immunosuppressive mechanisms to evade the immune system and whom were alive 2 years later. Although similar results were obtained
therefore be used as an immune-privileged “off the shelf” allogeneic in other studies, some failed to reach a positive outcome. An industry-
donor product for clinical applications. Several studies have suggested sponsored phase III randomized, placebo-controlled clinical trial for
that allogeneic MSCs are ignored by the immune system and/or are steroid-refractory acute GVHD in adults and children was completed
weakly immunogenic. For instance, the persistence of fetal MSCs in in 2009 and the results presented in February 2010 at the BMT
the bone marrow of the mothers was reported decades after pregnan- Tandem Meetings. Six infusions of industrial MSCs (Prochymal,
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cies. Baboons that received allogeneic MSCs injected at high doses Osiris Therapeutics) were administered at a dose of 2 × 10 MSCs/
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(5 × 10 MSCs/kg), first intravenously and then intramuscularly kg twice a week for 3–4 consecutive weeks, in addition to standard
developed alloantigen-specific antibodies but had reduced alloantigen- glucocorticoid therapy. The results that have been released to date
induced PBMC proliferation compared with naive controls, and demonstrate that in adults there was no statistical difference between
persistence of donor MSCs could be observed 4 weeks later. In MSCs and placebo on the overall response rate (35% vs. 30%; n =
contrast, other studies have suggested that MSCs can be fully recog- 244). Nevertheless, in a post-hoc analysis MSCs improved liver
nized by the immune system and/or support immune cell activation GVHD (day 100 response rates of 76% vs. 47%) or gastrointestinal
in an antigen-independent fashion, challenging the notion of immune GVHD (day 100 response rates of 82% vs. 68%). In pediatric
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privilege. In mice and pigs, allogeneic MSCs injected subcutane- patients, Prochymal showed a trend of improvement in durable CR
ously induced both alloantigen-specific T- and B-cell responses. In a rates (64% vs. 43%; n = 28), allowing for conditional approval of by
rat model of transplantation, allogeneic heart transplants were rejected Canadian and New Zealand authorities for use in children. 21
earlier if recipients were previously sensitized to donor MSCs. In Although numerous clinical studies using MSCs for the treatment
human MSCs, detailed analyses showed that in certain experimental of GVHD have been conducted, the mechanisms by which MSCs
conditions MSCs can support in vitro allogeneic T-cell proliferation, mediate their immunosuppressive effect against GVHD in humans
LPS- or antigen-induced IgG secretion by spleen B cells, or suppress is still unknown. It was described that acute GVHD is accompanied
neutrophil apoptosis. These events could be initiated through direct by a burst in cytokine production by activated donor immune cells,
antigenic recognition of MSCs and soluble factors produced by including IFN-γ and TNF-α. In a mouse model of GVHD using
MSCs, in particular IL-6. Paradoxically, IFN-γ stimulation of MSCs MSCs from iNOS-knock out mice, it was demonstrated that NO
enables them to acquire antigen-presenting cell-like features. Human produced by MSCs in response to the presence of high levels of
and mouse MSCs activated by IFN-γ upregulate MHC class I mol- IFN-γ was principally responsible for the immunosuppressive effect
ecule expression and MHC class I-mediated antigen presentation of observed. It was also shown that IFN-γ stimulation of MSCs is the
endogenously expressed viral proteins to cytotoxic T lymphocyte key element promoting the immunosuppressive effect of MSCs. The
lines. Expression of MHC class II molecules and antigenic presenta- latter study suggested that the effectiveness of MSC infusions to treat
+
tion to CD4 T cells was observed to be induced by IFN-γ, and mice undergoing allogeneic BM transplant varied with the phase of
depended in vitro on IFN-γ concentration. Antigenic presentation the disease and the level of circulating IFN-γ. Co-transplantation
+
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by mouse or human MSCs to CD8 or CD4 T lymphocytes induced of MSCs with HSCs did not prevent the appearance of GVHD,
IFN-γ and IL-2 production by T lymphocytes and T lymphocyte whereas MSC infusion 20 days post-HSC transplantation (when
proliferation. Antigen processing was not affected by sole treatment levels of IFN-γ are high) or implantation of prestimulated MSCs
with TNF-α, or TLR3 or TLR4 ligands. In addition, MSCs can with IFN-γ resulted in enhanced survival. Additional studies hinted
+
present extracellular soluble proteins to CD8 T cells through their that the timing of MSC administration relative to HSC transplant
MHC class I molecules. This function, a hallmark of professional may dramatically influence the outcome of both the graft-versus-
antigen-presenting cells, is known as cross-presentation and is critical leukemia (GVL) response and GVHD. Ning et al. reported results
for the mounting of a T-cell immune response targeted at extracellular from a clinical trial in which patients with hematological malignancy
pathogens or tumor antigens. Although MSCs do not express the underwent haploidentical peripheral blood stem cell (PBSC) trans-
classical B7 co-stimulatory molecules CD80 and CD86, they express plantation in combination with MSCs or not, where they observed
other surface molecules (ICAM and LFA-3) and cytokines (IL-6 and a reduction of GVHD in MSC-injected patients but also a 60%
IL-7), which can deliver co-stimulatory signals necessary for T-cell tumor relapse compared with a 20% relapse in the non-MSC
activation. group. 22

MESENCHYMAL STROMAL CELLS FOR THE PREVENTION MESENCHYMAL STROMAL CELLS TO PROMOTE
AND TREATMENT OF STEROID-REFRACTORY ACUTE HEMATOPOIETIC STEM CELL ENGRAFTMENT IN
GRAFT-VERSUS HOST DISEASE PRECLINICAL MODELS OF STEM CELL
TRANSPLANTATION
Based upon their dual role in supporting hematopoiesis and modulat-
ing immunity, MSCs have been studied as a companion transfusion Engraftment of HSCs is a considerable barrier to successful trans-
product for HSC transplantation (SCT), and can be categorized into plant, particularly in allogeneic SCT for nonmalignant diseases. Graft