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Clinical Development in Rare Diseases: Graft Versus Host disease Graft versus host disease (GvHD) is a generalised immune system reaction following allogeneic haematopoietic stem cell transplantation (AHSCT) in patients with acquired and congenital haematopoietic system disorders (e.g. lymphoid malignancies, dysmyelopoietic syndrome, bone marrow aplasia, etc.)1. GvHD is considered to affect approximately 0.5 in 10,000 people in the European Union (with a prevalence of around 26,000) and is thereby designated among rare diseases 2. Symptoms of GvHD were first described at the begining of the twentieth century by Murphy, but the underlying pathophysiology was not discovered until in the late 1950s; Simonsen differentiated the acute and chronic forms and introduced the name of graft versus host disease in the 1960s3.

a cut-off of 100 days6. Recently, due to different techniques for processing stem cells and administration of several adjuvant drugs during transplantation, manifestation of GvHD became more diverse and ’classic forms’ are often overlapping. It is reasonable to differentiate GvHD according to its existing features in whole, rather than its set of time or duration. In 2014, the National Institute of Health (NIH) released updated consensus criteria of both acute and chronic GvHDs7 as: Acute form – defined by the classic features (sunburn-like rashes, blisters on skin, diarrhoea, abdominal pain, blood in stool, nausea, vomiting, jaundice, dark urine, elevated serum bilirubin level, systemic infections, abdominal cramps) and manifested generally within 100 days after haematopoietic cell transplantation (HCT). A hyperacute form can develop within the first two weeks. Accidentally, the symptoms can return or persist more than 100 days post-HCT as late-phase ’acute’ GvHD.

Etiology and Pathogenesis The exact pathophysiology in the background of GvHD still remains incompletely understood. The main events can be characterised into three phases: tissue damage, called the afferent phase, followed by T-cell priming in the efferent phase, and then disease manifestation, as the effector phase. There are some determinants (risk factors) in the afferent phase4:

Chronic form – main features are skin thickening and rashes, joint pain and swelling, dry eyes, blurred vision, sore and pain in mouth, ocular, digestive and respiratory symptoms, diarrhoea, fatigue, and icterus8.

donor-recipient disparity, such as human leukocyte antigen (HLA) diversity, gender difference, other conditions e. g. multiparous female donors ineffective transplant conditioning/prophylactic regimen increased age (affecting either the recipient or the donor) pre-transplant comorbidities (e.g. peptic ulcer, obesity, diabetes, prior malignancy, cerebra-vascular disease, etc.)

The diagnosis of GvHD is based on clinical features (see above) and histologic confirmation: tissue biopsy (skin, gut, liver). There are no individual biomarkers yet for clinical application, but some serum proteins are possible options for diagnosis and prognosis of GvHD10:

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During the efferent phase, reactive T-cells in the graft recognise difference in histocompatibility antigens of recipient tissues, which activates the immune system and promotes secretion of inflammatory cytokines (predominantly IL-2 and IFN-gamma), enhance T-cell expansion, induce cytotoxic T-cells and natural killer cell responses and prime additional mononuclear phagocytes producing TNF-alpha and IL-1. The inflammatory cytokines initiate excessive production of chemokines, thus recruiting effector cells into target organs. Mononuclear phagocytes are triggered via a secondary signal provided by lipopolysaccharides that leak through the intestinal mucosa damaged during the initial phase1. This kind of cytokine ’storm’ drives the systemic inflammatory response leading to the effector phase reaction: expansive tissue injury and apoptosis, persisting inflammatory condition which, together with the activated cells drive the destruction and necrosis in the host body, complicated with general immune system dysregulation and organ dysfunction5. Clinical Manifestation and Diagnosis Historically, classification of GvHD was based on onset of symptoms and was divided into acute and chronic forms by 36 Journal for Clinical Studies

Overlap of acute and chronic form can also develop with features of both chronic GvHD and acute GvHD9.

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soluble IL-2-receptor-alpha (sIL-2Rα) concentrations are increased in aGVHD TNF receptor-1 reflects inflammation, correlates with clinical outcomes Hepatocyte growth factor (marker of epithelial apoptosis associated with intestinal and hepatic GvHD damage) have been suggested as a confirmatory tool for the diagnosis of acute GvHD at the onset of clinical symptoms and to provide prognostic information independent of GvHD severity ST2 (suppression of tumorogenicity 2) receptor is a member of the interleukin-1 receptor family) correlated with an increased risk of non-relapse mortality and resistance to treatment of acute GvHD REG-3-alpha (regenerating islet-derived 3-alpha) is expressed by regenerating cells in the gastrointestinal epithelium (especially Paneth cells), and its concentration increases in the bloodstream as a result of GvHD-associated epithelial mucosa injury

In all suspected cases, differential diagnosis of clinical features should be considered, e.g. rash (caused by drugs), diarrhoea (infections), hyperbilirubinemia (biliary sludge, drugs), etc11. Clinical Management (Prevention and Treatment) Presently, neither acute nor chronic GvHD can be 100% prevented, Volume 11 Issue 1

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