A modified model of graft-versus-host-induced systemic sclerosis (scleroderma) exhibits all major aspects of the human disease

OBJECTIVE: Diffuse systemic sclerosis (SSc; scleroderma) is a debilitating disease characterized by excessive dermal fibrosis with later progression to internal organs. In addition to the fibrotic component, major aspects of the disease include vascular or circulatory involvement and immune dysregulation evidenced by inflammatory cells in affected tissues and production of autoantibodies. Many animal models resembling this disease have been studied, including genetic models in mice and chickens, challenge with chemicals such as bleomycin or vinyl chloride to induce fibrosis, and models of graft-versus-host (GVH)-induced disease using certain strains of mice with differences in minor histocompatibility loci. The present studies were undertaken to determine if alteration of the induction of GVH-induced scleroderma could result in a model that more fully represented the human condition. METHODS: Disease was induced by injection of spleen cells from B10.D2 mice into BALB/c mice deficient in mature T and B cells (recombination-activating gene 2 targeted). Dermal thickening, collagen deposition, vasoconstriction, and parameters of immunity were analyzed. RESULTS: Similar to the human disease, this modified GVH model of SSc demonstrated evidence of dermal thickening, particularly in the extremities, progressive fibrosis of internal organs, vasoconstriction and altered expression of vascularity markers in skin and internal organs, early immune activation, inflammation in skin and internal organs, and autoantibody generation. CONCLUSION: This modified model of GVH-induced SSc exhibits all major components of human disease and is likely to contribute to better understanding of the disease mechanisms and, ultimately, improved treatments for patients.     

Pericardial disease in scleroderma (systemic sclerosis)

A review of the records of 210 patients with scleroderma seen between 1952 and 1972 revealed two clinical patterns of pericardial disease in 15 patients: (1) Chronic pericardial effusion (11 patients), confirmed by roentgenography and ultrasound, occurred in association with dyspnea, Raynaud's syndrome, cardiomegaly, congestive heart failure and pleural effusion in the absence of renal failure. In three patients hemodynamic signs of pulsus paradoxus, Kussmaul's sign or pulsus alternans developed. In six patients with chronic effusion renal failure developed within 6 months, an incidence severalfold higher than expected in the scleroderma population at large. (2) Acute pericarditis (four patients) was associated with dyspnea, chest pain, pericardial friction rub, fever, cardiomegaly and elevated latex fixation titers (in two of four patients).Pericardial disease is a recognizable clinical entity in scleroderma and should be considered in all patients with cardiomegaly, congestive heart failure or chest pain. In 34 autopsy studies, the incidence of pericardial involvement (62 per cent) exceeded the incidence of significant myocardial fibrosis (30 per cent); thus pericardial scleroderma represents a relatively common form of cardiac involvement in this diffuse connective tissue disease.     

Recombinant IL‐7/HGFβ hybrid cytokine separates acute graft‐versus‐host‐disease from graft‐versus‐tumour activity by altering donor T cell trafficking

Given that donor T cells from a transplant contribute both the desired graft‐versus‐tumour (GVT) effect and detrimental graft‐versus‐host disease (GVHD), strategies to separate GVHD and GVT activity are a major clinical goal. We have previously demonstrated that in vivo administration of a recombinant (r)IL‐7/HGFβ hybrid cytokine, consisting of interleukin‐7 (IL‐7, IL7) and the β‐chain of hepatocyte growth factor (HGFβ), significantly inhibits the growth of cancer cells in murine tumour models. The antit‐umour effect of rIL‐7/HGFβ is related to a marked infiltration T cells in the tumour tissues. We have also shown that GVHD was not induced in rIL‐7/HGFβ‐treated T cell‐depleted allogeneic haematopoietic stem cell transplantation (HSCT) recipients. We show here that, in T cell‐replete allogeneic HSCT murine models, rIL‐7/HGFβ attenuated acute GVHD (aGVHD), while promoting GVT activity. This was related to an alteration of donor T cell trafficking, with an increased infiltration of donor T cells into tumour tissues and the lympho‐haematopoietic system but decreased number of the T cells in the GVHD target organs. Therefore, rIL‐7/HGFβ may offer a new tool to alleviate aGVHD while prompting GVT, and to study the molecular regulation of T cell trafficking.     

Advances in understanding the pathogenesis of graft‐versus‐host disease

Allogeneic haematopoietic stem cell transplantation (HCT) is a potent immunotherapy with curative potential for several haematological disorders. Overcoming the immunological barrier of acute graft‐versus‐host disease (GVHD) remains a fundamental impediment to expanding the efficacy of HCT. GVHD reflects a complex pathological interaction between the innate and adaptive immune systems of the host and donor. Over the past decade there has been a tremendous advancement in our understanding of the cellular and molecular underpinnings of this devastating disease. In this review, we cover several recently appreciated facets of GVHD pathogenesis including novel extracellular mediators of inflammation, immune subsets, intracellular signal transduction, post‐translation modifications and epigenetic regulation. We begin to develop general themes regarding the immunological pathways in GVHD pathogenesis, discuss critical outstanding questions, and explore new avenues for GVHD treatment and prevention.     

Optimal management of chronic graft‐versus‐host disease in children

Chronic graft‐versus‐host disease (GVHD) is a major complication after allogeneic haematopoietic stem cell transplantation (HSCT). Not only is it the major cause of late mortality in HSCT patients, but it also accounts for significant morbidity. Much of the literature on chronic GVHD has focused on adults. Chronic GVHD is of major importance in children, especially since they have years to live following the complications of chronic GVHD and its therapy. The goal is to review incidence, manifestations, and therapies, especially when applicable to the paediatric population.     

Human papillomavirus reactivation following treatment of genital graft‐versus‐host disease

Vaginal chronic graft‐versus‐host disease (cGVHD) is a common complication of stem cell transplantation. Human papillomavirus (HPV) disease can reactivate after transplantation, presumably because of immune factors affecting systemic immunity, such as waning antibody titers, impaired T‐ and B‐lymphocyte responses, and the use of immunosuppressive therapies. However, a relationship between the use of local immunosuppressive agents and HPV reactivation and spread has not been previously described, to our knowledge. A 30‐year‐old woman, 2 years post transplant receiving systemic cyclosporine for cGVHD, was treated with vaginal dilators, topical corticosteroids, and estrogen for vaginal cGVHD. Colposcopy and biopsy for abnormal cytology revealed condylomatous cervicitis. Over the next 4 months, while continuing dilator therapy, linear verrucous lesions developed in the vagina and vulva, and were successfully treated with laser therapy. Use of local immunosuppression and dilators for genital GVHD can enhance spread of HPV infection. Integration of HPV screening and treatment into the care of women with genital cGVHD and development of strategies to manage both conditions simultaneously are warranted.     

Eosinophilic gastroenteritis and graft‐versus‐host disease induced by transmission of Norovirus with fecal microbiota transplant

Fecal microbiota transplantation (FMT) was performed to decolonize gastrointestinal tract from antibiotic‐resistant bacteria before allogeneic hematopoietic cells transplantation (alloHCT). AlloHCT was complicated by norovirus gastroenteritis, acute graft‐versus‐host disease, and eosinophilic pancolitis. Norovirus was identified in samples from FMT material. Symptoms resolved after steroids course and second norovirus‐free FMT from another donor.     

The implications of myelodysplastic syndrome – associated chromosomal abnormalities in the development of graft‐versus‐host disease

There is a growing body of evidences that acquired chromosomal abnormalities in bone marrow (BM) cells are associated with clinical manifestations of myelodysplastic syndrome (MDS). However, to our knowledge, there are no reports that describe the association between chromosomal abnormalities in MDS and graft‐versus‐host disease (GVHD) after allogeneic stem cell transplantation (allo‐SCT). Here, we describe two MDS cases with trisomy 8 and der(1;7)(q10;p10), who developed severe GVHD after allo‐SCT. We analyzed cytokine production and cell survival of monocytes from these patients with MDS before allo‐SCT, in comparison with healthy controls or an MDS patient with a different chromosomal abnormality, who has not developed GVHD. The monocytes from MDS patients with trisomy 8 and der(1;7)(q10;p10) produced a larger amount of pro‐inflammatory cytokine, tumor necrosis factor‐α, and a smaller amount of anti‐inflammatory cytokine, interleukin‐10, on stimulation with Toll‐like receptor (TLR) ligands. In addition, the monocytes from MDS cases with GVHD showed a decrease in apoptotic cell death upon stimulation with TLR ligands. We also detected host‐derived pro‐inflammatory antigen‐presenting cells (APCs) in skin GVHD lesions after allo‐SCT. These data suggest that trisomy 8 and der(1;7)(q10;p10) may be associated with the development of severe GVHD, by prolonging survival of pro‐inflammatory host‐derived APCs in GVHD lesions.     

Dermatopathic lymphadenopathy with Langerhans cell chimerism in graft‐versus‐host disease of the skin

Dermatopathic lymphadenopathy (DL) is well‐known in inflammatory skin disease; however, it has not been reported in graft‐versus‐host disease (GvHD) after allogeneic stem cell transplantation. Here, we report 2 cases of DL in patients with acute GvHD of the skin and demonstrate complete donor chimerism of Langerhans cells within the lymph nodes.     

Predictors of survival in systemic sclerosis (scleroderma)

We conducted followup of 264 patients with definite systemic sclerosis (SSc) who were entered into the multicenter Scleroderma Criteria Cooperative Study (SCCS) during 1973-1977. At the end of the study (average 5.2 years of followup), 38% were known to be alive, 50% were dead (68% of these deaths definitely related to SSc), and 12% were lost to followup. Survival analyses of 484 demographic, clinical, and laboratory items recorded at entry into the SCCS (within 2 years of physician diagnosis of SSc) were performed. Survival declined linearly, and the cumulative survival rate was less than 80% at 2 years, 50% at 8.5 years, and 30% at 12 years after entry. Analysis using combinations of entry variables identifying organ system involvement confirmed that renal, cardiac, pulmonary, and gastrointestinal involvement in SSc predicted reduced survival; however, data on organ system involvement at study entry could not be used to consistently predict which organ system would ultimately be involved as the primary cause of death. By survival tree analysis, the individual entry variables best predicting reduced survival included older age (greater than 64 years), reduced renal function (blood urea nitrogen greater than 16 mg/dl), anemia (hemoglobin less than or equal to 11 gm/dl), reduced pulmonary diffusing capacity for carbon monoxide (less than or equal to 50% of predicted), reduced total serum protein level (less than or equal to 6 gm/dl), and reduced pulmonary reserve (forced vital capacity less than 80% with hemoglobin greater than 14 gm/dl or forced vital capacity less than 65% with hemoglobin less than or equal to 14 gm/dl). Cox proportional hazards model analysis confirmed these results. Different combinations of variables led to markedly different survival rates. The poorest prospects for survival were in patients with SSc who were less than or equal to 64 years old with a hemoglobin level less than or equal to 11 gm/dl, and in those greater than 64 years old with a blood urea nitrogen level greater than 16 mg/dl. These results may be useful in predicting individual patients at risk for shortened survival.     

The cardiovascular manifestations of systemic sclerosis (scleroderma)

In conclusion, systemic sclerosis is both a fascinating and frustrating affliction. It is a systemic disease of multiple stages. Prognosis is dependent on the site and extent of visceral involvement. There is evidence to implicate the vascular system as the primary target organ of the disease. The cardiovascular manifestations include myocardial fibrosis, pericarditis, and a variety of arrhythmias and conduction abnormalities. Intractable heart failure or sudden cardiac death can ensue. Cardiac involvement in systemic sclerosis portends an ominous prognosis, and is probably most directly related to the extent of myocardial fibrosis which is present. The pathogenesis of myocardial fibrosis has not been determined, but it appears to be a result of an impairment of myocardial perfusion at both the small artery and microvasculature level. Obstructive, vasospastic, and devascularization factors all may be playing a role.     

Prevention of acute graft‐versus‐host disease by humanized anti‐CD26 monoclonal antibody

CD26 (DPP4) is a T cell costimulatory molecule as well as T cell activation marker, and CD26⁺ T cells are accumulated in inflamed tissues, such as rheumatoid synovitis and autoimmune thyroiditis. In the present study, we found accumulation of CD26⁺ T cells in graft‐versus‐host disease (GVHD) target organs. To expand our in vitro findings to an in vivo system, we examined CD26‐dependent organ injury in a xenogeneic GVHD (x‐GVHD) murine model. Following intraperitoneal injection of human peripheral blood mononuclear cells into non‐obese diabetic severe combined immunodeficiency/γ_c^?/? mice (hu‐PBL‐NOG mice), the mice exhibited the onset of GVHD symptoms associated with the presence of CD26^high human lymphocytes in the peripheral blood and GVHD target tissues. Administration of humanized anti‐human CD26 monoclonal antibody (mAb) decreased x‐GVHD severity and prolonged survival in hu‐PBL‐NOG mice without loss of engraftment of human T cells, while increasing doses of CTLA4‐ immunoglobulin fusion protein diminished engraftment of human lymphocytes. Importantly, anti‐CD26 mAb treatment preserved the graft‐versus‐leukaemia effects in studies using cotransplantation of P815 murine leukaemic cells. In addition, CD26⁺ lymphocytes infiltrated the GVHD patients' target tissues. Altogether, our data indicate a role for CD26 in the regulation of GVHD and point to CD26 as a novel target for therapeutic intervention in this disease.