Immune Deficiency States Research Articles

Molecular Pathways: Molecular Basis for Sensitivity and Resistance to JAK Kinase Inhibitors

Janus-activated kinases (JAK) are the mediators of a variety of cytokine signals via their cognate receptors that result in activation of intracellular signaling pathways. Alterations in JAK1, JAK2, JAK3, and TYK2 signaling contribute to different disease states, and dysregulated JAK-STAT signaling is associated with hematologic malignancies, autoimmune disorders, and immune-deficient conditions. Genetic alterations of JAK2 occur in the majority of patients with myeloproliferative neoplasms and occur in a subset of patients with acute leukemias. JAK-mediated signaling critically relies on STAT transcription factors, and on activation of the MAPK and PI3K/Akt signaling axes. Hyperactive JAK at the apex of these potent oncogenic signaling pathways therefore represents an important target for small-molecule kinase inhibitors in different disease states. The JAK1/2 inhibitor ruxolitinib and the JAK3 inhibitor tofacitinib were recently approved for the treatment of myelofibrosis and rheumatoid arthritis, respectively, and additional ATP-competitive JAK inhibitors are in clinical development. Although these agents show clinical activity, the ability of these JAK inhibitors to induce clinical/molecular remissions in hematologic malignancies seems limited and resistance upon chronic drug exposure is seen. Alternative modes of targeting JAK2 such as allosteric kinase inhibition or HSP90 inhibition are under evaluation, as is the use of histone deacetylase inhibitors. Combination therapy approaches integrating inhibition of STAT, PI3K/Akt, and MAPK pathways with JAK kinase inhibitors might be critical to overcome malignancies characterized by dysregulated JAK signaling.

Coexistent hairy cell leukaemia and hepatosplenic t-cell lymphoma: a case report

BackgroundHairy cell leukaemia (HCL) is a chronic B-cell leukaemia characterized by expansion of neoplastic cells in the spleen, bone marrow and blood. Symptoms of HCL are related to pancytopenia and immune deficiency. Patients with HCL have an increased risk of second malignancy either in a form of synchronous disease or in a form of an increased incidence of a second neoplasm after the treatment of HCL. Hepatosplenic T-cell lymphoma (HSTCL) is a rare form of aggressive extranodal T-cell lymphoma. Its pathogenesis is connected to a chronic immune deficiency status and its coexistence with other neoplasms is practically non-existent.CaseWe present a case of a 53-year-old female patient suffering from hepatosplenomegaly, peripheral lymphadenopathy and related B symptoms. An excisional biopsy of the enlarged axillary lymph node revealed partial infiltration with CD3+/CD56+/TIA + T cell lymphoma. Bone marrow trephine biopsy and flow cytometric immunophenotypization of bone marrow cells and peripheral blood showed presence of two types of neoplastic cells in the peripheral blood and in the bone marrow (composite lymphoma). One of them showed typical morphologic characteristics and immunohistochemical features of HCL, while another one was morphologically and immunophenotypically consistent with the diagnosis of HSTCL, respectively. The patient was treated with multivalent chemotherapy including rituximab but all treatments turned out to be only partially effective. While HCL responded to the treatment, HSTCL was refractory to the chemotherapy and the patient died 7 months after the initial diagnosis because of haematemesis induced by Mallory-Weiss syndrome.ConclusionThis is the first recorded case of coexistent HCL and HSTCL in the same patient. A multidisciplinary approach, encompassing careful morphology interpretation, immunophenotypic, cytogenetic and molecular analyses, is mandatory to obtain an accurate diagnosis of composite lymphoma.Virtual slidesThe virtual slides for this article can be found here: http://www.diagnosticpathology.diagnomx.eu/vs/9354870531161685.

Mycological Studies on the Sputa of HIV Positive Clients Attending HIV Clinic in Federal Medical Centre Owerri, Nigeria

Background: Human immune deficiency virus (HIV), the causative agent of Acquired Immune Deficiency Syndrome (AIDS) has remained a global cankerworm, with more impact in the sub-Saharan Africa. This virus destroys and depletes the human CD4 cells, leading to immune deficiency state and making the individual susceptible to opportunistic infections. Fungal opportunistic infections are among the common pathogens seen earlier in HIV positive individuals and may present as respiratory diseases like Pneumocystis jiroveci pneumonia and pulmonary cryptococcosis. This study aimed at understanding the pattern of fungal opportunists in the sputa of HIV positive individuals in our locality, to understand the demographics among those with the fungal isolates and to correlate CD4 level of the patients with the isolated opportunistic fungal pathogens. Methods: This was a prospective study in design, study area was Federal Medical Centre Owerri, Imo state, Nigeria, and study population included HIV positive individuals who were older than fifteen (15) years who developed cough lasting for more than fourteen (14) days). The hospital is the largest in the state and serves some neighbouring states like Rivers, Anambra and Abia state. The sample size was seventy three (73). Samples were collected, processed and organisms identified and results tabulated. Results: Out of the seventy three (73) sputa sample, 50 (68.5%) showed positive growth while twenty three 23 (31.5%) did not show any growth. Males with opportunistic fungal infections had a lower frequency (40%) than females (60%). 40/50 (80%) of the grown organisms were Candida organism and 23/40 (57.5%) of them were albicans. Candida albican had the highest incidence 23/50 (46%) and seen more in the age bracket (25-34). It was also rarely seen when the CD4 cell count was more than 500 cell/mm3 but very common when count was <400 cells/ mm3. Cryptococcus neoformans had 5/50 (10%) and isolated in individual with CD4 count<100 cells/mm3, Aspergillus flavus and A. fumigatus were isolated at 56 and 367 cells/mm3 with incidences of 2.0% respectively (Figure 1). The Penicillium marneffi reported as the emerging fungal infection among HIV clients in Southeast Asia was not seen in our series. Conclusions: Most pulmonary fungal opportunistic infection in the setting of HIV often mimics pulmonary tuberculosis. Candida albicans has the highest incidence in our study. However, knowledge of fungal opportunistic infections pattern in HIV patients will help clinicians in the appropriate management of the clients—in terms of prophylaxis and therapeutics.

Diffuse Renal Cortical Echogenic Foci in a Patient With AIDS

Pneumocystis jirovecii is ubiquitous in the environment and is best known as the cause of Pneumocystis pneumonia (PCP) in immune-suppressed hosts. Extrapulmonary P. jirovecii is a rare complication of this opportunistic infection primarily seen in patients with immune-deficient states. Nephritis due to P. jirovecii was first described by Bargman in 1991 in a patient with atypical nephrocalcinosis found on conventional radiography. This case report presents a patient with Pneumocystis nephritis and describes the sonographic appearance as well as the advantages of sonography in the early detection of this uncommon condition.

Virtual screening of m3 protein antagonists for finding a model to study the gammaherpesvirus damaged immune system and chemokine related diseases.

M3 protein is a chemokine decoy receptor involved in pathogenesis of persistent infection with gammaherpesvirus and complications related to the latency of this pathogen. We proposed that antagonists of the M3 would provide a unique opportunity for studying new therapeutic strategies in disordered immune system, immune-deficient states and role of chemokines in pathogenesis development. Comparative modeling and fold recognition algorithms have been used for prediction of M3 protein 3-D model. Evaluation of the models using Q-mean and ProSA-web score, has led to choosing predicted model by fold recognition algorithm as the best model which was minimized regarding energy level using Molegro Virtual Docker 2011.4.3.0 (MVD) software. Pockets and active sites of model were recognized using MVD cavity detection, and MetaPocket algorithms. Ten thousand compounds accessible on KEGG database were screened; MVD was used for computer simulated docking study; MolDock SE was selected as docking scoring function and final results were evaluated based on MolDock and Re-rank score. Docking data suggested that prilocaine, which is generally applied as a topical anesthetic, binds strongly to 3-D model of M3 protein. This study proposes that prilocaine is a potential inhibitor of M3 protein and possibly has immune enhancing properties.

Next-generation-sequencing-spectratyping reveals public T-cell receptor repertoires in pediatric very severe aplastic anemia and identifies a chain CDR3 sequence associated with hepatitis-induced pathogenesis

Current diagnostic approaches that characterize T-cell deficiency by analyzing diversity of T-cell receptor sequences effectuate limited informational gain about the actual restrictiveness. For deeper insight into T-cell receptor repertoires we developed next-generation-sequencing-spectratyping, which employs high coverage Roche/454 sequencing of T-cell receptor (β)-chain amplicons. For automated analysis of high-throughput-sequencing data, we developed a freely available software, the TCR profiler. Gene usage, length, encoded amino acid sequence and sequence diversity of the complementarity determining region 3 were determined and comprehensively integrated into a novel complexity score. Repertoires of CD8(+) T cells from children with idiopathic or hepatitis-induced very severe aplastic anemia (n=7), children two months after bone marrow transplantation (n=7) and healthy controls (children n=5, adults n=5) were analyzed. Complexity scores clearly distinguished between healthy and diseased, and even between different immune deficiency states. The repertoire of aplastic anemia patients was dominated by public (i.e. present in more than one person) T-cell receptor clonotypes, whereas only 0.2% or 1.9% were public in normal children and adults, respectively. The CDR3 sequence ASSGVGFSGANVLT was highly prevalent in 3 cases of hepatitis-induced anemia (15-32% of all sequences), but was only low expressed in idiopathic aplastic anemia (2-5%, n=4) or healthy controls (<1%). Fifteen high frequent sequences were present exclusively in aplastic anemia patients. Next-generation-sequencing-spectratyping allows in-depth analysis of T-cell receptor repertoires and their restriction in clinical samples. A dominating clonotype was identified in hepatitis-induced anemia that may be associated with disease pathogenesis and several aplastic-anemia-associated, putatively autoreactive clonotypes were sequenced.

TNF Inhibitors Are Associated with Higher Risk for Melanoma in Rheumatoid Arthritis Patients

Immune deficiency states, such as immunosuppression for organ transplantation, are associated with elevated risk for malignant melanoma. Although use

Herpesviruses and the microbiome

The focus of this article will be to examine the role of common herpesviruses as a component of the microbiome of atopic patients and to review clinical observations suggesting that atopic patients might be predisposed to more severe and atypical herpes-related illness because their immune response is biased toward a TH2 cytokine profile. Human populations are infected with 8 herpesviruses, including herpes simplex virus HSV1 and HSV2 (also termed HHV1 and HHV2), varicella zoster virus (VZV or HHV3), EBV (HHV4), cytomegalovirus (HHV5), HHV6, HHV7, and Kaposi sarcoma-associated herpesvirus (termed KSV or HHV8). Herpesviruses are highly adapted to lifelong infection of their human hosts and thus can be considered a component of the human "microbiome" in addition to their role in illness triggered by primary infection. HSV1 and HSV2 infection and reactivation can present with more severe cutaneous symptoms termed eczema herpeticum in the atopic population, similar to the more severe eczema vaccinatum, and drug reaction with eosinophilia and systemic symptoms syndrome (DRESS) is associated with reactivation of HSV6 and possibly other herpesviruses in both atopic and nonatopic patients. In this review evidence is reviewed that primary infection with herpesviruses may have an atypical presentation in the atopic patient and conversely that childhood infection might alter the atopic phenotype. Reactivation of latent herpesviruses can directly alter host cytokine profiles through viral expression of cytokine-like proteins, such as IL-10 (EBV) or IL-6 (cytomegalovirus and HHV8), viral encoded and secreted siRNA and microRNAs, and modulation of expression of host transcription pathways, such as nuclear factor κB. Physicians caring for allergic and atopic populations should be aware of common and uncommon presentations of herpes-related disease in atopic patients to provide accurate diagnosis and avoid unnecessary laboratory testing or incorrect diagnosis of other conditions, such as drug allergy or autoimmune disease. Antiviral therapy and vaccines should be administered promptly when indicated clinically.

Patterns of patient specific dosimetry in total body irradiation

Total body irradiation (TBI) has been used for bone marrow transplant for hematologic and immune deficiency conditions. The goal of TBI is to deliver a homogeneous dose to the entire body, with a generally accepted range of dose uniformity being within ± 10% of the prescribed dose. The moving table technique for TBI could make dose uniform in whole body by adjusting couch speed. However, it is difficult to accurately estimate the actual dose by calculation and hence in vivo dosimetry (IVD) is routinely performed. Here, the authors present patterns of patient-specific IVD in 161 TBI patients treated at our institution. Cobalt-60 teletherapy unit (Model C9 Cobalt-60 teletherapy unit, Picker X-ray Corporation) with customized moving bed (SITI Industrial Products, Inc., Fishers, IN) were used for TBI treatment. During treatment, OneDose(TM) (Sicel Technology, NC) Metal Oxide-silicon Semiconductor Field Effect Transistor detectors were placed at patient body surface; both entrance and exit side of the beam at patient head, neck, mediastinum, umbilicus, and knee to estimate midplane dose. When large differences (>10%) between the prescribed and measured dose were observed, dose delivery was corrected for subsequent fractions by the adjustment of couch speed and/or bolus placement. Under IRB exempt status, the authors retrospectively analyzed the treatment records of 161 patients who received TBI treatment between 2006 and 2011. Across the entire cohort, the median ± SD (range) percent variance between calculated and measured dose for head, neck, mediastinum, umbilicus, and knee was -2.3 ± 10.2% (-66.2 to +35.3), 1.1 ± 11.5% (-62.2 to +40.3), -1.9 ± 9.5% (-66.4 to +46.6), -1.1 ± 7.2% (-35.2 to +42.9), and 3.4 ± 12.2% (-47.9 to +108.5), respectively. More than half of treatments were within ± 10% of the prescribed dose for all anatomical regions. For 80% of treatments (10%-90%), dose at the umbilicus was within ± 10%. However, some large differences greater than 35% were also found at several points. For one case, the knee received double the prescribed dose. When the dose differences for multiple fractions were averaged, compliance (± 1 0%) between the prescription and measured dose was improved compared to the dose difference of the first single fraction, for example, as at umbilicus, which improved from 83.9% to 98.5%. Actual dose measurement analysis of TBI patients revealed a potentially wide variance from the calculated dose. Based from their IVD method for TBI using Cobalt-60 irradiator and moving table, ± 10% over entire body is hard to achieve. However, it can be significantly improved with immediate feedback after the first fraction prior to subsequent treatments.

Short-term central venous catheter complications in patients with sickle cell disease who undergo apheresis

Patients with sickle cell disease (SCD) are prone to develop thrombosis and infection due to their inflammatory and immune deficiency state. These patients require red cell exchange therapy for treatment or prevention of hemoglobin S associated complications. Owing to vascular access problems, adult patients need central venous catheterization (CVC) for exchange procedures. Procedure related complications have been reported for long-term CVCs in pediatric patients. However, short-term CVC complications in adult patients are not clear. This report represents the results of documented complications of short-term CVCs in patients with SCD who undergo apheresis. A total of 142 non-tunneled catheters with average median diameter of 9F (range 8-16F) were implanted for apheresis. The catheters were mainly inserted through the right internal jugular vein (66.2%). Total days of catheter were 412. Results were reported as a complication rate and event according to 1,000 catheter days and compared to a control group including 37 healthy stem cell donors. In the patient group, 1 (1%) hematoma and 1 (1%) infection were observed for internal jugular vein catheterization (3.7 hemorrhages and 3.7 infections according to 1,000 catheter days), whereas four (8.9%) cases of thrombosis and 1 (2.2%) infection (27 and 6.9 according to 1,000 catheter days) developed in femoral vein. There was a significant difference in terms of thrombosis (P=0.009). In the control group, only individual developed thrombosis in internal jugular vein. Short-term CVC inserted through to the internal jugular vein seems to be safer than femoral vein in patients with SCD.

Prevalence of Demodex folliculorum and Demodex brevis in childhood malnutrition and malignancy

Hair follicle mites, Demodex folliculorum and Demodex brevis, are known to accompany immune-deficiency states, however no study so far has investigated their presence in malnutrition. In this study we aimed to determine the prevalence of those mites in childhood malnutrition, malignancy and risk factors. One hundred children with malnutrition, 31 children with malignancy and 63 children without any chronic disease and infection were included in this study. History, physical examination, anthropometric measurements and routine laboratory findings were recorded. Demodex spp. were investigated by standard superficial skin biopsies. Demodex was found in 25 patients (25%), 10 patients (32.3%), and one patient (1.6%) among malnutrition, malignancy, and control groups, respectively (P = 0.001). By using multilogistic regression binary method, it was found that malnutrition, malignancy and low socioeconomic level increased the risk 17.37 times (P = 0.006), 27.29 times (P = 0.002), and 2.3 times (P = 0.037), respectively. Of 22 children who were evaluated after 6 months, 13 (59.1%) were negative for Demodex. In 11 (84.6%) of those 13, nutritional status was improved. Demodex was detected in approximately in one-quarter and one-third of children with malnutrition and malignancy, respectively. Eliminating the cause of immunosuppression, such as poor nutritional status, seems also to be an effective method for eliminating Demodex.

Inflammatory bowel disease: An archetype disorder of outer environment sensor systems.

The pathogenesis of the two inflammatory bowel diseases (IBDs) phenotypes ulcerative colitis (UC) and Crohn's disease (CD) has remained elusive, thus frustrating attempts at defining a cure. IBD often presents as a complex inflammatory process wherein colon lesions (UC) or widespread ulceration and fissure (CD) might be accompanied by ancillary extra-intestinal manifestations involving the eye, skin, joints or liver, but also by full-blown "autoimmune" disorders from psoriasis and multiple sclerosis to rheumatoid arthritis; attempts at unraveling a link or a hierarchical order in these entities have proven almost fruitless. More recently, the input of genetics has suggested that the IBDs might be multi-organ inflammatory processes, elicited by a large number of low-penetrance susceptibility genes, with environmental factors needed to induce full-blown disease. At a noteworthy exception to this rule, the description of the nucleotide-oligomerization domain (NOD) gene mutations in CD came at the beginning of the 2000s: the NOD-LRR are part of a highly conserved microbial sensor system which respond to bacterial peptidoglycans by mounting an inflammatory response. At least in Caucasian patients, the prevalently loss-of-function mutation of NOD permitted to unexpectedly define CD as an immune deficiency state, and upon its recent description in apparently unrelated disorders such as the Blau syndrome (a granulomatous pediatric syndrome), and perhaps in psoriasis and chronic obstructive pulmonary disorders, has contributed to revolutionize our view of IBD and CD in particular. The latter affection, together with psoriasis and chronic pulmonary disease can now be included into a newly identified category named "barrier organ disease", wherein a barrier organ is defined as a large mucosal or epithelial surface with an abundant metagenomic microbial population and an underneath reactive tissue, the whole structure being in contact with the outer environment and capable to react to it. Personalized treatments and empowerment of research across different disease phenotypes should be the advantages of this novel mindset.

Rhino-Orbital Mucormycosis in Diabetes Mellitus

Rhino-orbital mucormycosis is a rare but life threatening infection that generally occurs in patients with diabetes mellitus and other immune deficiency conditions. Rhino-orbital and Rhino-cerebral are two form of the disease. As such the condition is a medical emergency. Early recognition and treatment are essential because it may lead to death in few days. Fungal infection of nasal cavity is uncommon but is being seen with increasing frequency in patients with immune deficiency.

Splenic tuberculosis presenting as fever of unknown origin with severe neutropenia

Fever of undetermined origin always poses a challenging problem to the physician. Tuberculosis is an important health problem in developing countries. It is mostly seen in immune-compromised patients. And it is one of the common causes of fever of unknown origin. I am reporting a case of a splenic tuberculosis in 48 years old male who is not known of any immune deficiency state, he was presented with 3 weeks history of fever and found to have severe neutropenia and with negative work up for all hematological, rheumatological and malignant causes. A computerized tomography scan of the abdomen confirmed splenic enlargement with multiples hypo dense lesions consist with either splenic infection or splenic lymphoma so exploratory splenectomy was performed. Histological examination revealed granulomatouse inflammation with numerous acid fast bacilli consist with tuberculosis. He was started on four anti-tuberculouse drugs. in less than one week his fever subside with normalization of his neutrophilic count

Spontaneous Hepatocellular Adenoma in Paediatric Age Group – Case Report

Hepatocellular adenoma (Hca) is a rare, benign, liver cell tumour. Hca is most frequently seen in women with a history of oral contraceptive use. Hca is also reported in children with glycogen storage disorders, galactosaemia, Hurler's syndrome, severe immune deficiency states, diabetes mellitus, sex hormone disturbances, Fanconis anaemia, in those who are on androgen therapy and also in seizure disorder patients who are on carbamazepine therapy. Usually, Hca arises typically in a clinical setting of hormonal or metabolic abnormalities which stimulate hepatocyte proliferation. Though it is rare, a few cases of spontaneous Hca have been reported in children and also in adults, which were not associated with any of the known risk factors which are associated with Hca. Hca has to be differentiated from focal nodular hyperplasia, hepatocellular carcinoma and hepatoblastoma. The histological features and the assessment of cell proliferation by using immuno histochemistry, help in confirming the diagnosis of Hca. In a few cases of Hca, malignant transformations have been reported. Hence, a careful search for malignant transformations is necessary. In this report, we have documented two cases of spontaneous Hca which occurred in two normal children.

Innate immune cells are dispensable for regenerative growth of imaginal discs

Following tissue damage the immune response, including inflammation, has been considered an inevitable condition to build the host defense against invading pathogens. The recruitment of innate immune leukocytes to injured tissue is observed in both vertebrates and invertebrates. However, it is still not conclusive whether the inflammatory response is also indispensable for the wound healing process by itself, in addition to its role in microbial clearance. In this study we determine the requirement of innate immune cells, both hemocytes and fat body cells, in Drosophila imaginal disc regeneration. We investigate wound healing and regenerative cell proliferation of damaged imaginal discs under immunodeficient conditions. To delay development of Drosophila at matured third instar larval stage we used a sterol-mutant erg2 knock-out yeast strain in the medium. This dietary-controlled developmental arrest allowed us to generate larvae free of immune cells without interfering with their larval development. In addition, this approach allowed uncoupling regenerative cell proliferation of damaged discs from their normal developmental growth. We furthermore examined the regenerative cell proliferation of fragmented imaginal discs by transplantation into host flies deficient of immune cells. We demonstrate that the damaged/fragmented discs in immune cells deficient conditions still exhibit regenerative cell proliferation comparable to those of control samples. These results suggest that recruitment of immune cells is not a prerequisite for the regenerative growth of damaged imaginal discs.

900 Nutri-Medicinal Plants for Manangement of Children Diseases in Uganda: Case Study of Namungalwe Sub County, Iganga District

Nutrition deficiency is a key determinant of an immune deficient body state. There is scientific evidence that plant species effective in disease management confers both nutritional and medicinal benefits to...

A review on human toxoplasmosis

Toxoplasmosis is a worldwide infection caused by the intracellular parasite Toxoplasma gondii. At least a third of the world human population are infected with the parasite, making it one of the most successful parasitic infections. Primary maternal infection may cause health-threatening sequelae for the foetus, or even cause death in uterus. Reactivation of a latent infection in immune deficiency conditions such as AIDS and organ transplantation can cause fatal toxoplasmic encephalitis. Toxoplasmosis is a major cause of retinochoroiditis, especially in individuals with an impaired immune system. Despite the usually 'asymptomatic' nature of the infection, a significant burden imposed by the parasite necessitates the implementation of effective means for the prevention, diagnosis, and management of this disease. Laboratory diagnosis, i.e. PCR and serologic assays, plays the main role in the diagnosis of congenital infection and assists in the confirmatory diagnosis of toxoplasmic encephalitis and ocular toxoplasmosis. Here, we briefly review general aspects of Toxoplasma infection and focus on the diagnostic methods currently used in medical laboratories for the diagnosis of Toxoplasma infection.

Diagnosis of pulmonary mucormycosis aiding the diagnosis of small cell lung cancer

Mucormycosis is a rare complication in immunocompromised patients. Antemortem diagnosis of mucormycosis is difficult and often incorrect. We report a case of pulmonary mucormycosis caused by Cunninghamella bertholletiae in an elderly man with interstitial pneumonia. The diagnosis of mucormycosis was established by bronchoalveolar lavage. A coexisting immune deficiency condition was considered. Lung cancer was suspected because of an elevated progastrin-releasing peptide level and bilateral hilar and mediastinal lymphadenopathy; it was diagnosed after performing endoscopic ultrasound-guided fine-needle aspiration. Treatment by intravenous liposomal amphotericin B was effective, but relapse occurred because of bone marrow suppression caused by chemotherapy for lung cancer. Treatment for mucormycosis was resumed, but the patient died of carcinomatous lymphangiosis. Autopsy confirmed the diagnosis of pulmonary mucormycosis and revealed refractory anaemia with small cell lung cancer. Mucormycosis often occurs in immunocompromised patients, but this case is rare because the mucormycosis was diagnosed before the diagnosis of malignancy. Because prognosis is often poor, the possibility of coexisting malignancies should always be investigated in patients with mucormycosis infections.

The case for intrauterine stem cell transplantation

The clinical burden imposed by the collective group of monogenic disorders demands novel therapies that are effective at achieving phenotypic cure early in the disease process before the development of permanent organ damage. This is important for lethal diseases and also for non-perinatally lethal conditions that are characterised by severe disability with little prospect of postnatal cure. Where postnatal treatments are limited to palliative options, intrauterine stem-cell therapies may offer the potential to arrest pathogenesis in the early undamaged fetus. Intrauterine stem-cell transplantation has been attempted for a variety of diseases, but has only been successful in immune deficiency states in the presence of a competitive advantage for donor cells. This disappointing clinical record requires preclinical investigations into strategies that improve donor cell engraftment, including optimising the donor cell source and manipulating the microenvironment to facilitate homing. This chapter aims to outline the current challenges of intrauterine stem-cell therapy.