|Year : 2020 | Volume
| Issue : 3 | Page : 88-93
Mesenchymal stem cell and hematopoietic stem cell transplantation for vasculitis
Center of Laboratory Medicine, Union Hospital of Fujian Medical University, Fuzhou, Fujian 350001, China
|Date of Submission||29-Jun-2020|
|Date of Decision||15-Jul-2020|
|Date of Acceptance||29-Jul-2020|
|Date of Web Publication||26-Aug-2020|
Dr. Lianming Liao
Center of Laboratory Medicine, Union Hospital of Fujian Medical University, Fuzhou, No. 29, Xinquan Road, Fuzhou, Fujian 350001
Source of Support: None, Conflict of Interest: None
Vasculitis is a great therapeutic challenge. Currently, no effective treatments are available. Although biologics are emerging as new therapeutic alternatives, steroids remain the mainstay of the treatment. Similar to other immune-mediated diseases, refractory vasculitis seems to be a potential target of both bone marrow and mesenchymal stem cell transplantation. Preliminary data show stem cell-based therapies are effective for several types of vasculitis that are steroid-refractory. However, clinical data are sparse due to the limited number of patients. More studies are needed to confirm the preliminary results. In addition, optimization of the therapeutical regimens of stem cell transplantation is necessary in future.
Keywords: Hematopoietic stem cell transplantation, mesenchymal stem cell, vasculitis
|How to cite this article:|
Liao L. Mesenchymal stem cell and hematopoietic stem cell transplantation for vasculitis. Vasc Invest Ther 2020;3:88-93
| Introduction|| |
Vasculitis is pathologically characterized by inflammation and necrosis of vessels. More than 30 kinds of vasculitis have been reported according to an international consensus. Different types of vasculitis involve blood vessels in locations throughout the body. The symptoms of vasculitis depend on the particular blood vessels that are involved by the inflammatory process. For example, giant cell arteritis (GCA) typically involves the medium- to large-sized blood vessels supplying the head and neck, but rarely involves the blood vessels of the kidneys. In contrast, Wegener's Granulomatosis with polyangiitis (GPA) frequently involves the blood vessels of the kidneys, the lungs, and the upper respiratory tract, but rarely involves the blood vessels to the brain. Vasculitis may present as a primary process or as a complication of some other diseases and conditions. Primary vasculitis is relatively rare but is associated with significant morbidity and mortality, particularly if diagnosis is delayed. Secondary vasculitis may accompany collagen-vascular, rheumatic, infectious, or malignant diseases.
The underlying mechanism of vasculitis is still illusive. Many risk factors of vasculitis have been reported, including geography, age, ethnicity, gender, genetic factors, and environmental factors. For example, Behcet disease is more common in countries along the ancient Silk Route. Takayasu disease is more prevalent in South Asian countries and in children 5 years of age, and in the female. GCA and GPA occur predominantly in Caucasian populations. Studies have found there is a strong association between hepatitis B and polyarteritis nodosa (PAN), hepatitis C and mixed cryoglobulinemia, and silica dust and pauci-immune vasculitis.
The selection of treatment regimens depends on the type and severity of vasculitis. Treatment generally includes three parts: remission induction, remission maintenance, and monitoring. Glucocorticoids are the first-line treatment for vasculitis. A variety of immunosuppressive medications, newer biologic agents and new treatment regimens have been introduced in recent years to address this unmet medical need, which includes methotrexate, azathioprine, mycophenolate, cyclophosphamide, rituximab, intravenous immunoglobulin (IVIG), and plasma exchange.
| Mesenchymal Stem Cell Characteristics|| |
Mesenchymal stem cells (MSCs), also known as mesenchymal stromal cells, are adult stem cells capable of differentiation into adipocytes, chondroblasts, and osteoblasts. MSCs were originally isolated from bone marrow and later from a variety of tissues, such as adipose tissue, tooth pulps, periodontal tissue, umbilical cord, and placenta. In 2006, the International Society for Cellular Therapy recommended a set of minimal criteria for MSCs. First, MSC must be plastic-adherent when maintained in standard culture conditions using tissue culture flasks. Second, ≥95% of the MSC population must express CD105, CD73, and CD90. In addition, these cells must lack expression (≤2% positive) of CD45, CD34, CD14 or CD11b, CD79α or CD19, and HLA class II. Third, the cells must be able to differentiate to osteoblasts, adipocytes, and chondroblasts under standardin vitro differentiating conditions.
MSCs from different origins have immunoregulatory properties. MSCs exhibit capabilities such as prompting T-cell expansion to a regulatory phenotype, shifting macrophages to anti-inflammatory and immunosuppressive M2 phenotypes, inhibiting dendritic cells maturation, and inhibiting functions of natural killer cells, B-cells, and memory T-cells.,,, The immunoregulatory properties of MSCs have been harnessed to treat a variety of autoimmune diseases.
Importantly, MSCs may migrate to the damaged tissue and secrete a number of cytokines and chemokines through paracrine and exosome mechanisms. The secreted cytokines and chemokines include vascular endothelial growth factor, stromal cell-derived factor-1, fibroblast growth factor, insulin-like growth factor, keratinocyte growth factor, hepatocyte growth factor, and vascular endothelial growth factors. In addition, MSCs can transfer mitochondria, functional proteins, mRNAs, and microRNAs into the damaged cells through microvesicle-dependent cell-to-cell communication. Finally, MSCs secrete immunosuppressive factors consisting of IDO, TSG6, NO, interleukin-10 (IL-10), CCL2, galectins, prostaglandin E2, and transforming growth factor-β. These all help repair damaged cells and tissues by regulating the local immune response.
After numerous in-vitro and in-vivo preclinical studies, autologous and allogeneic MSCs have been applied in a range of immune-mediated conditions, including graft versus host disease, Crohn's disease, type 1 diabetes, multiple sclerosis, refractory systemic lupus erythematosus, and systemic sclerosis. Hypothetically, MSCs may be beneficial for vasculitis by reducing inflammation, inducing prosurvival genes, and downregulating pro-apoptotic genes of the vascular endothelial cells.
| Hematopoietic Stem Cell Characteristics|| |
Vasculitis may develop into a chronic, relapsing-remitting autoimmune disease. Therefore, an ideal therapeutic goal is to switch off the autoimmune-induced inflammation and halt disease progression. Immunoablation and reconstitution of the immune system via hematopoietic stem cell transplantation (HSCT) is a more intensive approach than immunosuppressants. This approach can switch off the autoreactive, inflammatory process, and restoring self-tolerance.
HSCT has been used to treat various autoimmune disorders refractory to conventional immunosuppression therapy, including systemic sclerosis, systemic lupus erythematosus, rheumatoid and Crohn's disease, for several decades. The purpose of HSCT in the treatment of autoimmune diseases is to cause severe immunosuppression or even total immunoablation. Infused stem cells then repopulate the patient and reconstitute hematopoiesis and a complete immune system. In allogeneic HSCT, the new immune system is provided by the donor hematopoietic stem cells.
| Henoch–schönlein Purpura Iga Vasculitis|| |
IgA vasculitis is the new term for Henoch-Schönlein purpura (HSP) and is the most common systemic vasculitis in childhood. It is defined as vasculitis with IgA1-dominant immune deposits affecting small vessels (predominantly capillaries, venules, or arterioles). HSP is associated with glomerulonephritis, which is indistinguishable from IgA nephropathy. Children with microscopic hematuria without renal dysfunction or proteinuria and those with nonpersistent mild-moderate proteinuria usually do not require any specific therapeutic intervention other than a “watchful waiting approach” since the prognosis is excellent. HSP-associated arthritis responds well to nonsteroidal anti-inflammatory drugs. Severe skin lesions and gastrointestinal involvement can be alleviated with a short course of corticosteroids. However, corticosteroids do not prevent renal disease. Immunosuppressants, including azathioprine, mycophenolate mofetil (MMF), or intravenous cyclophosphamide, may be considered as second-line agents.
Mu et al. reported a 12-year-old boy treated with cord-derived MSCs for liver cirrhosis and refractory HSP. The patient presented with purpura in the skin of the bilateral lower limbs and thrombocytopenia. He had a chronic itching skin rash for the past 2 years and received prednisone treatment. At admission, ultrasonography of the abdomen showed diffuse lesions and multiple solid nodules in the liver. Abdominal computed tomography showed hepatomegaly with small nodules under the right lobe of the liver and enlarged splenic sinuses. The patient received MSC transplantation for eight times in 2 months. Then methylprednisolone was tapered off after 1 month with the disappearance of skin rash and normalization of platelet count and liver transaminase level. Abdominal ultrasound showed fewer round nodules in the liver and decreased spleen size. Follow-up at 6 months revealed there were no skin rash and no nodules in the liver, and the platelet count remained normal. This is a rare case of HSP with thrombocytopenia and liver cirrhosis that responded to MSC treatment.
| Anca-Associated Vasculitis|| |
Antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV) comprises (GPA, previously referred to as Wegener's granulomatosis), microscopic polyangiitis, eosinophilic granulomatous polyangiitis, and renal-limited vasculitis. GPA may present sequentially as a predominantly granulomatous form or as an acute small vessel vasculitic form. These two presentations may also co-exist.
There is a rapid expansion in the therapeutic agents for AAV, including purine, pyrimidine, MMF, leflunomide, 15-deoxyspergualin, immunoglobulin, tumor necrosis factor-alpha (TNF-α) antagonism infliximab, IL-5 antagonism mepolizumab, rituximab (for induction of B-lymphocyte depletion), alemtuzumab (for induction for T-lymphocyte depletion), and anti-thymocyte globulin (for induction for T-lymphocyte depletion). Because AAV is associated with abnormal immune function, immunoablation and HSCT to switch off the autoreactive, inflammatory process of the patients is reasonable.
In a phase 1/2 trial of autologous peripheral blood stem cell transplantation for refractory autoimmune disease, one patient with GPA was enrolled. The patient was male and 21 years old. He has been treated with corticosteroids, cyclophosphamide, and cyclosporin A before. Peripheral blood stem cells were mobilized with granulocyte colony-stimulating factor after administration of cyclophosphamide (2 g/m2) for 2 days. 5 × 106 CD34+ cells/kg were collected by apheresis and infused. After hematopoietic reconstitution, the size of the left orbital granuloma decreased substantially, and exophthalmos was reduced. Monthly steroid pulse therapy was discontinued. At 3 months after transplantation, serum proteinase 3 (PR3)-anti neutrophil cytoplasmic antibodies (ANCA) level decreased to 39 IU/ml, which was 72 IU/ml before transplantation. However, it increased again to 157 IU/ml at 12 months. Thus, autologous peripheral blood stem cell transplantation is promising in short term why GPA relapses in the long-term remain unclear.
In addition, an international meeting in 2000 reported four patients with GPA receiving autologous peripheral stem cell transplantation. All patients experienced an initial complete response, but two patients relapsed at 2.3 and 3 years, respectively. However, the detailed treatment protocol was not described.
Secondary autoimmune diseases are an intriguing complication after autologous stem cell transplantations. For example, p-ANCA-associated vasculitis was induced in a 43-year-old male who had received autologous stem cell transplantation for systemic sclerosis. The patient received a conditioning regimen with cyclophosphamide and anti-thymocyte globulin before receiving cyclophosphamide and granulocyte-colony-stimulating factor mobilized-stem cell transplantation. He responded well to HSCT. One year and 4 months after transplantation, mild erythrocyturia without acanthocytes and proteinuria was seen on routine urinalysis. During the following year, erythrocyturia increased to 131 erythrocytes/μl and protein excretion to 628 mg/g creatinine. Renal biopsy revealed mild global and focal-segmental sclerosing and focal-segmental proliferative glomerulonephritis. A diagnosis of p-ANCA-positive glomerulonephritis was made. The patient responded well to Rituximab treatment.
| Kawasaki Disease|| |
Kawasaki disease (KD) is a systemic inflammatory disease that predominantly affects medium- and small-sized arteries. The principal clinical features of KD include polymorphous exanthema and acute non-purulent cervical lymphadenopathy, which are the manifestation of abnormal immune function.
The early diagnosis of KD is crucial. Treatment with aspirin and IVIG is effective. However, up to 20% of patients develop IVIG resistance. Other treatments include corticosteroids and corticosteroids plus IVIG. In some case reports, anti-TNF-α, anakinra, plasmapheresis and immunoglobulin plus ciclosporin were shown to be effective.
Most recently, Uchimura et al. evaluated if adipose-derived MSCs could suppress KD-associated vasculitis in animals with Candida albicans water-soluble fraction (CAWS)-induced severe coronary arteritis. Candida albicans-derived substances, such as CAWS fraction, induce coronary arteritis, similar to KD in mice. Mice were treated with intravenous MSCs or phosphate-buffered saline. On day 29, the mice were sacrificed. MSC infusion significantly inhibited coronary arteritis and decreased the levels of pro-inflammatory cytokines IL-1β, IL-12, IL-17, RANTES, INF-γ, and TNF-α. Most importantly, MSC infusion improved animal survival. These findings highlight that MSC transplantation is potentially a novel therapeutic strategy for severe KD due to their anti-inflammatory and immune regulatory functions.
| Polyarteritis Nodosa|| |
PAN is characterized by necrotizing vasculitis in medium-or small-sized arteries or angiographic abnormalities. Patients may also have other symptoms of skin, muscle, kidneys, gastrointestinal tract, and heart. Drugs for severe PAN include corticosteroids, cyclophosphamide, and MMF. Despite therapy, mortality remains high. Biologic agents, including rituximab, are also described for children with systemic PAN.
Similar to other autoimmune disorders, intense immunosuppression followed by the reconstitution of the immune system with HSCT has been proposed as a last-line treatment. A 22-year old Caucasian female was diagnosed with juvenile-onset PAN. Over the following 8 years, she had multiple flares of disease which could not be controlled by oral and i.v. corticosteroids, cyclophosphamide (to a total dose of 51 g), oral colchicine, IVIG and plasmapheresis. She suffered increasingly frequent flares, and repeat angiography showed new aneurysms in the hepatic arteries in the past 18 months. She was therefore offered autologous HSCT. After the administration of cyclophosphamide (1.5 g/m2), hematopoietic stem cells were harvested by leucopheresis after stem cell mobilization with granulocyte-colony stimulating factor from the bone marrow. CD34+ cells were purified by magnetic bead selection. Immunosuppressive conditioning regimen was 20 mg CAMPATH-1H (days − 9 to − 5), fludarabine 30 mg/m2 (days − 8 to − 4), and cyclophosphamide 1 g/m2 on days − 3 and − 2. After HSCT, she remained well and discontinued immunosuppressive medication other than low-dose prednisolone (<10 mg/day) for the next 5 months. Unfortunately, she developed a new vasculitic rash on the lower extremities that were not present before HSCT over the ensuing year. Fourteen months after HSCT, she developed autoimmune hyperthyroidism. In addition, she was positive for thyroglobulin antibodies and p-ANCA. At 18 months, the patient developed autoimmune thrombocytopenia. The platelet count recovered with IVIG and oral steroids. By sequence-specific T-cell receptor heteroduplex analysis of purified T-cell subsets, the researchers showed that clonal T-cell expansions, present within 2 months of HSCT when the majority of the T-cells express CD45RO+, were subsequently within the CD45RA+ T-cell subset at 1 year after HSCT. These data suggested that T-cells underwent reversion from CD45RO+ to CD45RA+. Thus, in patients who may have a genetic background that predisposes them to autoimmunity, immune reconstitution after HSCT can be associated with new autoimmune phenomena.
| Takayasu Arteritis|| |
Takayasu arteritis (TA) is characterized by large-vessel vasculitis. The clinical diagnosis of TA is usually challenging. Due to the nonspecific symptoms and the absence of specific laboratory parameters, TA is often unrecognized in the acute early phase. The general therapeutic approach is the induction of remission (high dose corticosteroid combined with another immunosuppressant), followed by maintenance therapy (lower dose corticosteroid combined with a maintenance immunosuppressive agent, usually methotrexate). About half of patients respond to steroids, and the nonresponders may benefit from other forms of immunosuppression. In addition, methotrexate, azathioprine, MMF, leflunomide, chlorambucil, antimalarials, and cyclophosphamide have been used in children as first- or second-line agents. Biologic therapies, including anti TNFα mAb and tocilizumab (a monoclonal antibody against interleukin 6 receptor) were reported to be effective.,
Autologous HSCT for TA was reported in a Brazilian woman. She was diagnosed in June 1990 when she was 41 years old. The arteriography showed irregularities and stenosis of the abdominal aorta. The patient was treated with various immunosuppressive agents, such as steroids, oral cyclophosphamide, MMF, methotrexate, and chlorambucil, but all of those therapies failed. In October 2002, a magnetic resonance angiogram showed narrowing and irregularities in both carotid and subclavian arteries and in the brachiocephalic artery. She received autologous HSCT in April 2003 due to the worsening of clinical symptoms. Hematopoietic stem cells were mobilized with cyclophosphamide (2 g/m2) and granulocyte colony-stimulating factor. Conditioning regimen included cyclophosphamide (50 mg/kg/day × 4) plus rabbit anti-thymocyte globulin. The patients responded well to HSCT. There was complete resolution of headache, dizziness, and malaise while limb claudication was significantly reduced. Sixty days after HSCT, magnetic resonance angiography showed correction of the stenosis of the brachiocephalic artery and reduction in the irregularities of the left carotid artery and of the left subclavian artery. On day 320, arterial pulses of the left lower limbs and of the carotid arteries showed normal shape and speed by Doppler US, and the wave speed of abdominal aorta increased to 73 cm/s. The surprisingly immediate improvement in artery structure and function was unexpected and deserved further studies.
| Deficiency of Adenosine Deaminase Type 2|| |
Deficiency of adenosine deaminase type 2 (DADA2) is an autosomal recessive disease resembling PAN and is caused by mutations in the CECR1 gene., The principal clinical manifestations include livedo racemosa, vasculitic peripheral neuropathy, digital ischemia, and cutaneous ulceration. Anti-TNF-α mAb is particularly useful for this form of monogenic vasculitis.
Allogeneic HSCT has been reported to be successful in a DADA2 patient at 6 months of age. He had a homozygous mutation in CECR1 (p.R169Q). He underwent HSCT in 2003 from a matched unrelated donor after myeloablative conditioning. The patient showed rapid immune reconstitution, with the resolution of cytopenias, skin lesions, hepatosplenomegaly, and hypercoagulability and recovery of serum ADA2 levels to the normal range for his age. MRI revealed the disappearance of vasculopathy changes in the brain. The absence of vasculopathy and the resolution of hypercoagulability after HSCT suggest that the correction of ADA2 blood levels reduces macrophage activation and endothelial disruption, both of which probably contribute to vasculitis. This patient's younger brother also presented with DADA2 in 2009 at 6 years of age and received anti-TNF-α mAb (etanercept). Although his clinical condition was stable, he has persisting profound lymphopenia and low-grade inflammation.
Patients with DADA2 demonstrate skewed macrophage development toward the M1 pro-inflammatory phenotype as opposed to the M2 anti-inflammatory phenotype. M1 macrophages are known to produce TNF-α, which explains why anti-TNF-α mAb seems particularly effective in DADA2. Because MSCs may skew macrophage from M1 to M2 phenotype, we hypothesize that MSCs may be beneficial for DADA2 patients. Future clinical trials are needed to support our hypothesis.
| Chronic Atypical Neutrophilic Dermatosis With Lipodystrophy and Elevated Temperature and (Sting)-Associated Vasculitis of Infancy|| |
CANDLE syndrome (Chronic Atypical Neutrophilic Dermatosis with Lipodystrophy and Elevated temperature) is a recessive disease caused by gene mutations in the proteasome pathway, and is classified as a proteasome-associated autoinflammatory syndrome. Mutations in PSMB8, PSMB4, PSMB9, PSMA3, and POMP are proposed to be responsible for CANDLE syndrome. Effective treatments for CANDLE syndrome are still not available. Oral corticosteroids, methotrexate, cyclosporine, azathioprine, or IVIGs have achieved some improvements. CANDLE is associated with dysregulated type I interferon production, therefore targeting this pathway with selective JAK1/2 kinase inhibitor baricitinib has been proposed, and a treatment protocol has been started.
Stimulator of interferon genes (STING)-associated vasculitis of infancy (SAVI) arises from sporadic/dominant mutation in the TMEM173 gene and presents early in life with vasculitic rash in the cheeks, nose, and peripheries. Cutaneous vasculitis and deteriorating lung function usually continue throughout childhood, with the development of pulmonary hypertension and lung fibrosis, often with fatal outcome. Early treatment targeting the interferon pathway (e.g. with JAK inhibitors) may offer some benefits to the patients.
Although no clinical trials have been reported for CANDLE and SAVI with either MSCs or HSCT, we consider that both strategies may be helpful in alleviating the patients' symptoms and improve their quality of life.
| Conclusion|| |
Considerable therapeutic advances for the treatment of vasculitis have been made in the past 20 years, including the application of MSCs and HSCT. As new treatments that facilitate corticosteroid-sparing are emergently needed, more trials are expected to confirm the preliminary results of MSCs and HSCT. However, it is a great challenge to enrol enough patients for trials aiming the rare diseases. Thus international cooperation is necessary in future.
Financial support and sponsorship
The project was supported by the Natural Science-‚Foundation of Fujian Province of China (Grant number: 2018J01302) and Joint Funds for the Innovation of Science and Technology, Fujian Province (Grant number: 2017Y9001).
Conflicts of interest
There are no conflicts of interest.
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