Shape of the art: TCR-repertoire after allogeneic hematopoietic cell transplantation.

The human adaptive immune repertoire is characterized by specificity and diversity to provide immunity against past and future tasks. Such tasks are mainly infections but also malignant transformations of cells. With its multiple lines of defense, the human immune system contains both, rapid reaction forces and the potential to capture, disassemble and analyze strange structures in order to teach the adaptive immune system and mount a specific immune response. Prevention and mitigation of autoimmunity is of equal importance. In the context of allogeneic hematopoietic cell transplantation (HCT) specific challenges exist with the transfer of cells from the adapted donor immune system to the immunosuppressed recipient. Those challenges are immunogenetic disparity between donor and host, reconstitution of immunity early after HCT by expansion of mature immune effector cells, and impaired thymic function, if the recipient is an adult (as it is the case in most HCTs). The possibility to characterize the adaptive immune repertoire by massively parallel sequencing of T-cell receptor gene rearrangements allows for a much more detailed characterization of the T-cell repertoire. In addition, high-dimensional characterization of immune effector cells based on their immunophenotype and single cell RNA sequencing allow for much deeper insights in adaptive immune responses. We here review, existing - still incomplete - information on immune reconstitution after allogeneic HCT. Building on the technological advances much deeper insights into immune recovery after HCT and adaptive immune responses and can be expected in the coming years.

Endocrine health in survivors of adult-onset cancer.

Long-term survivors of cancer (ie, the patient who is considered cured or for whom the disease is under long-term control and unlikely to recur) are at an increased risk of developing endocrine complications such as hypothalamic-pituitary dysfunctions, hypogonadisms, osteoporosis, or metabolic disorders, particularly when intensive tumour-directed therapies are applied. Symptom severity associated with these conditions ranges from mild and subclinical to highly detrimental, affecting individual health and quality of life. Although they are usually manageable, many of these endocrine pathologies remain underdiagnosed and untreated for years. To address this challenge, a higher degree of awareness, standardised screening tools, comprehensible treatment algorithms, and a close collaborative effort between endocrinologists and oncologists are essential to early identify patients who are at risk, and to implement appropriate treatment protocols. This Review highlights common symptoms and conditions related to endocrine disorders among survivors of adult-onset cancer, provides a summary of the currently available practice guidelines, and proposes a practical approach to diagnose affected patients among this group.

Potential of TCR sequencing in graft-versus-host disease.

Graft-versus-host disease (GvHD) remains one of the major complications following allogeneic haematopoietic stem cell transplantation (allo-HSCT). GvHD can occur in almost every tissue, with the skin, liver, and intestines being the mainly affected organs. T cells are implicated in initiating GvHD. T cells identify a broad range of antigens and mediate the immune response through receptors on their surfaces (T cell receptors, TCRs). The composition of TCRs within a T cell population defines the TCR repertoire of an individual, and this repertoire represents exposure to self and non-self proteins. Monitoring the changes in the TCR repertoire using TCR sequencing can provide an indication of the dynamics of a T cell population. Monitoring the frequency and specificities of specific TCR clonotypes longitudinally in different conditions and specimens (peripheral blood, GvHD-affected tissue samples) can provide insights into factors modulating immune reactions following allogeneic transplantation and will help to understand the underlying mechanisms mediating GvHD. This review provides insights into current studies of the TCR repertoire in GvHD and potential future clinical implications of TCR sequencing.

Established and Emerging Treatments of Skin GvHD.

Graft-versus-host disease (GvHD) of the skin is a severe allo-immune reaction and complication following allogeneic stem cell transplantation. Over the past years, intensive pre-clinical research has led to an improved understanding of the pathophysiology of acute and to a lesser extend chronic GvHD. This has translated into the approval of several new agents for the treatment of both forms of GvHD. This review summarizes the most recent advances in underlying pathomechanisms, clinical trials and newly approved agents for GvHD, with a special focus on skin involvement.

Skeletal health in patients following allogeneic hematopoietic cell transplantation.

Allogeneic hematopoietic cell transplantation (HCT) is a potentially curative approach for patients with certain hematological diseases, including several forms of lymphoma and leukemia. Besides several treatment-associated risks, transplanted patients are at an increased risk of developing osteoporosis. The underlying pathophysiology is complex and includes factors influenced directly by the disease as well as applied therapies like irradiation, chemotherapy and adjuvant immunosuppressive agents. In addition, patients are prone to secondary hypogonadism, and many patients will require long-term glucocorticoid therapy to mitigate graft-versus-host reactions. All these factors contribute to bone loss, but the individual risk profile may vary greatly. This review summarizes our knowledge on bone loss following allogenic HCT and provides screening and treatment recommendations.

T-cell receptor-α repertoire of CD8+ T cells following allogeneic stem cell transplantation using next-generation sequencing.

Alloreactivity or opportunistic infections following allogeneic stem cell transplantation are difficult to predict and contribute to post-transplantation mortality. How these immune reactions result in changes to the T-cell receptor repertoire remains largely unknown. Using next-generation sequencing, the T-cell receptor alpha (TRα) repertoire of naïve and memory CD8+ T cells from 25 patients who had received different forms of allogeneic transplantation was analyzed. In parallel, reconstitution of the CD8+/CD4+ T-cell subsets was mapped using flow cytometry. When comparing the influence of anti-T-cell therapy, a delay in the reconstitution of the naïve CD8+ T-cell repertoire was observed in patients who received in vivo T-cell depletion using antithymocyte globulin or post-transplantation cyclophosphamide in case of haploidentical transplantation. Sequencing of the TRα identified a repertoire consisting of more dominant clonotypes (>1% of reads) in these patients at 6 and 18 months post transplantation. When comparing donor and recipient, approximately 50% and approximately 80% of the donors' memory repertoire were later retrieved in the naïve and memory CD8+ T-cell receptor repertoire of the recipients, respectively. Although there was a remarkable expansion of single clones observed in the recipients' memory CD8+ TRα repertoire, no clear association between graft-versus-host disease or cytomegalovirus infection and T-cell receptor diversity was identified. A lower TRα diversity was observed in recipients of a cytomegalovirus-seropositive donor (P=0.014). These findings suggest that CD8+ T-cell reconstitution in transplanted patients is influenced by the use of T-cell depletion or immunosuppression and the donor repertoire.