Diagnosis and staging of ophthalmic manifestations of the graft-versus-host reaction after allogeneic hematopoietic stem cell transplantation

Graft-versus-host reaction is a common complication of allogeneic hematopoietic stem cell transplantation. This condition develops in approximately 4070% of patients. Its most common clinical manifestations include xerotic keratoconjunctivitis and cicatricial conjunctivitis. It is important to correctly diagnose and classify the ocular condition after surgery. Ocular graft-versus-host reaction can present as either classic acute or chronic form, acute form with late onset or with overlap syndrome. It may lead to severe ocular surface disease, which can significantly decrease the quality of life and restrict daily activities of patients. It is thus important to monitor the ocular condition closely since with early diagnosis of the condition and timely treatment start, risks of irreversible damage could be diminished. This article is dedicated to modern criteria of diagnosis and staging of ocular graft-versus-host reaction.

Efficient adoptive transfer of autologous modified B cells: a new humanized platform mouse model for testing B cells reprogramming therapies

Here, we report a novel experimental setup to perform adoptive transfer of gene-edited B cells using humanized immune system mice by infusing autologous HIS mouse-derived human B cells “educated” in a murine context and thus rendered tolerant to the host. The present approach presents two advantages over the conventional humanized PBMC mouse models: (i) it circumvents the risk of xenogeneic graft-versus-host reaction and (ii) it mimics more closely human immune responses, thus favoring clinical translation. We show that the frequencies and numbers of transduced B cells in recipient’s spleens one week post-transfer are within the range of the size of the pre-immune B cell population specific for a given protein antigen in the mouse. They are also compatible with the B cell numbers required to elicit a sizeable immune response upon immunization. Altogether, our findings pave the way for future studies aiming at assessing therapeutic interventions involving B cell reprogramming for instance by an antibody transgene in a “humanized” hematopoietic setting.

Consequence of Histoincompatibility beyond GvH-Reaction in Cytomegalovirus Disease Associated with Allogeneic Hematopoietic Cell Transplantation: Change of Paradigm

Hematopoietic cell (HC) transplantation (HCT) is the last resort to cure hematopoietic malignancies that are refractory to standard therapies. Hematoablative treatment aims at wiping out tumor cells as completely as possible to avoid leukemia/lymphoma relapse. This treatment inevitably co-depletes cells of hematopoietic cell lineages, including differentiated cells that constitute the immune system. HCT reconstitutes hematopoiesis and thus, eventually, also antiviral effector cells. In cases of an unrelated donor, that is, in allogeneic HCT, HLA-matching is performed to minimize the risk of graft-versus-host reaction and disease (GvHR/D), but a mismatch in minor histocompatibility antigens (minor HAg) is unavoidable. The transient immunodeficiency in the period between hematoablative treatment and reconstitution by HCT gives latent cytomegalovirus (CMV) the chance to reactivate from latently infected donor HC or from latently infected organs of the recipient, or from both. Clinical experience shows that HLA and/or minor-HAg mismatches increase the risk of complications from CMV. Recent results challenge the widespread, though never proven, view of a mechanistic link between GvHR/D and CMV. Instead, new evidence suggests that histoincompatibility promotes CMV disease by inducing non-cognate transplantation tolerance that inhibits an efficient reconstitution of high-avidity CD8+ T cells capable of recognizing and resolving cytopathogenic tissue infection.

Amenorrhoea with XY karyotype postbone marrow transplant

A 17-year-old girl presented with secondary amenorrhoea. She developed normal age-appropriate secondary sexual characteristics and attained menarche at the age of 13 years. One year following her menarche, she was diagnosed with acute myeloid leukaemia and was treated with chemotherapy, total body radiation and bone marrow transplant with complete remission. The matched donor was her elder male sibling. Her evaluation for secondary amenorrhoea included full hormonal analysis and pelvic ultrasound scan. These suggested hypergonadotrophic hypogonadism with a normal uterus and ovaries. Peripheral leucocyte karyotype as part of routine hypogonadism workup was found to be 46 XY. The differential diagnosis of Swyer syndrome, which entails surgical removal of gonads due to the high risk of gonadoblastoma, was raised initially before reviewing the laboratory results of previous chromosomal analysis. Considering her medical history, the amenorrhoea was finally attributed to ovarian insufficiency due to chemotherapy and radiotherapy. The 46 XY karyotyping could be explained by the bone marrow transplant received from her donor brother. Hypogonadism causing amenorrhoea is commonly encountered after chemoradiotherapy. Pretreatment and post-treatment chromosomal analysis is essential in such cases. Karyotyping could be misleading especially if the patient suffered from graft-versus-host reaction post gender mismatched bone marrow transplant.

New genome editing technologies in the treatment of X-linked adrenoleukodystrophy

X-linked adrenoleukodystrophy is a severe progressive neurological disease that is predominantly found in male patients and caused by mutations in the X-linked ABCD1 gene encoding peroxisome transport protein. The disease is clinically characterized by two main phenotypes: the most severe infant cerebral form and adrenomyeloneuropathy. The disease is treated by allogeneic transplantation of hematopoietic cells from a healthy donor to stop progression, and gene therapy with a self-activating lentiviral vector, the carrier of the functional gene ABCD1. Each method has its own limitations. The authors present and theoretically substantiate an alternative approach to the treatment of adrenoleukodystrophy; they propose to modify the autologous CD34+ cells from the patient using genomic editing, in order to replace the mutant DNA sequence of ABCD1 gene with a wild-type sequence, while replacing the mutant protein in the edited cells. The edited autologous CD34+ cells can be introduced by their transplantation into the bone marrow or by a series of repeated intravenous infusions. This method will allow avoiding both the search for a donor and the graft-versus-host reaction

The role of NOD2/CARD15 gene of antigen-presenting system in functioning of various organs and systems

The article presents the literature review devoted to NOD2/CARD15 gene. Genetic variability affects the susceptibility and development of certain human diseases such as autoimmune diseases and infections, affecting numerous cellular processes, and thus modulating the response to environmental and internal factors. The NOD2/CARD15 gene plays a major role in the development and course of various diseases such as Grohn's disease, Blau syndrome, as well as the risk of developing severe complications of the graft versus host reaction after allogeneic stem cell transplantation. NOD (Nucleotide Oligomerization Domain) is the domain of nucleotide oligomerization. NOD-like receptors play an important regulatory role in the response on infectious agents and at activation of the adaptive immune response. It is known that the mechanism of action of NOD-like receptors is based on the response to the pathogen of associated molecular patterns mainly of bacterial origin, which leads to the formation and activation of inflammasome. Recently, another NOD-like receptor activation mechanism has been revealed that provides innate virus recognition. The review presents Toll-like receptors, which are part of the innate immune system. Innate immunity is an inherited system of protection of the body against pathogenic and non-pathogenic microorganisms. The mechanisms of innate immunity develop very quickly. In newborns, the immune system is mainly dependent on components of the innate or antigen-independent immune system including phagocytes, natural killer cells, antigen-presenting cells, humoral inflammatory mediators and complement system.

Historical background of umbilical stem cell culture

Umbilical cord is a waste material, and therefore does not raise ethical concerns related to its use for research and medicine. Stem cells from umbilical cord have a significant advantage over cells from other sources. First, the umbilical cord is an infinite source of stem cells, because it can be taken theoretically during each delivery. Secondly, acquisition of umbilical cord is a non-invasive, safe procedure for mother and child. Thirdly, the transplantation of umbilical cord stem cells is associated with a lower risk of infection and a less-frequent “graft versus host” reaction. In this work, the authors present a historical background of research on the cell from its discovery to modern times characterized by highly advanced methods of obtaining stem cells from umbilical cord and from other sources.

Clinical case of curing a generalized adenovirus infection on the background of graft versus host reaction in a child after bone marrow transplantation from a haploidentical donor

Adenovirus infection is one of the causes of transplant-associated mortality after allogeneic hematopoietic stem cell transplantation. Fulminant liver failure with adenovirus infection is a diagnostic and therapeutic problem due to its aggressive clinical course and extremely poor prognosis, while modern methods of treating adenovirus infection are based on the use of virostatic drugs and virus-specific lymphocytes and are associated with severe side effects. The article presents a rare clinical case of elimination of disseminated adenoviral infection with fulminantly developing liver failure in a patient after allogeneic bone marrow transplantation from a haploidentical donor.

Current Approaches to Engineering of NK Cells for Cancer Immunotherapy

Natural Killer (NK) cells belong to a unique subtype of lymphocytes with a great potential for cancer immunotherapy due to their ability to rapidly recognize and efficiently kill tumor cells. Their anti-cancer potential can be further increased by genetic and non-genetic modifications. However, the attempts of genetic improvements of NK cells over the past 20 years have been hampered by the difficulties of gene delivery into this cell type, thus preventing researchers from producing clinically relevant numbers of viable and biologically active NK cells. Currently, several successful approaches to genetic modification of NK cells have been described, and clinically applicable cell therapy products have been characterized. Now that we understand much better the ways of NK cell optimization to enhance their tumor regression-inducing capabilities, novel approaches to engineering NK surface receptors are being developed. In this review, we focus on the advantages and perspectives of various approaches to modification of NK cells. Positive results of several preclinical studies are described, demonstrating that genetically modified NK cells can be comparable to therapeutic T cells in their efficiency of recognizing and destroying tumor targets. Moreover, using allogenic NK cells to treat a number of cancer types might have even wider and eager clinical adoption than cytotoxic T cells due to a much decreased risk of graft versus host reaction inherent in NK cell-based immunotherapeutic products.