Abstract:Background: Mismatched stem cell transplantation is associated with a high risk of graft loss, graft-versus-host disease (GvHD), and transplant-related mortality. Alternative graft manipulation strategies have been used over the last 11 years to reduce these risks. Objective: We investigated the outcome of using different graft manipulation strategies among children with primary immunodeficiencies. Methods: Between 2006 and 2017, 147 patients with primary immunodeficiencies received 155 mismatched grafts: 30 T… Show more
“…Since most forms of PID are based on monogenetic defects intrinsic to hematopoietic cells ( 15 ), the treatment of primary immunodeficiency by replacing the mutated cells with healthy donor hematopoietic stem cells and establishing alloimmunity is a potentially curative approach. Based on proper strategies in selection of a suitable donor ( 16 – 19 ) and GvHD prophylaxis, reduced intensity conditioning regimes ( 20 ) and better supportive care overall survival reaches up to 85% today even for patients who undergo transplantation in young adulthood ( 21 ).…”
Common variable immunodeficiency (CVID) is the most common primary immunodeficiency in adults. It is associated with hypogammaglobulinemia, recurring infections and autoimmune phenomena. Treatment includes immunoglobulin substitution and immunosuppressants. Autoimmune neurological manifestations of CVID are rare and occur predominantly as granulomatous disease. We report the case of a 35-year-old woman with CVID who developed autoimmune encephalitis as demonstrated by double cerebral biopsy. Infectious or malignant causes could be excluded. Despite intensive immunosuppressive therapy with common regimens no significant improvement could be achieved. Ultimately, an autologous hematopoietic stem cell transplantation (HSCT) was performed, resulting in lasting complete remission of the encephalitis. To our knowledge, this is the first report of refractory autoimmune phenomena in CVID treated by autologous HSCT.
“…Since most forms of PID are based on monogenetic defects intrinsic to hematopoietic cells ( 15 ), the treatment of primary immunodeficiency by replacing the mutated cells with healthy donor hematopoietic stem cells and establishing alloimmunity is a potentially curative approach. Based on proper strategies in selection of a suitable donor ( 16 – 19 ) and GvHD prophylaxis, reduced intensity conditioning regimes ( 20 ) and better supportive care overall survival reaches up to 85% today even for patients who undergo transplantation in young adulthood ( 21 ).…”
Common variable immunodeficiency (CVID) is the most common primary immunodeficiency in adults. It is associated with hypogammaglobulinemia, recurring infections and autoimmune phenomena. Treatment includes immunoglobulin substitution and immunosuppressants. Autoimmune neurological manifestations of CVID are rare and occur predominantly as granulomatous disease. We report the case of a 35-year-old woman with CVID who developed autoimmune encephalitis as demonstrated by double cerebral biopsy. Infectious or malignant causes could be excluded. Despite intensive immunosuppressive therapy with common regimens no significant improvement could be achieved. Ultimately, an autologous hematopoietic stem cell transplantation (HSCT) was performed, resulting in lasting complete remission of the encephalitis. To our knowledge, this is the first report of refractory autoimmune phenomena in CVID treated by autologous HSCT.
“…But even when no HLA-matched (related or unrelated) donor can be found, valid alternatives are now available. Key studies demonstrated remarkable survival in PID cohorts, using haplo-identical transplants with selective ex vivo depletion of αβ T lymphocytes, which are directly involved in graft versus host disease (GVHD), and B cells, which may harbor Epstein–Barr virus (EBV), thus preserving passive innate immunity from the donor and allowing for a faster time to full immune reconstitution (11–14). Re-infusion of genetically modified αβ T lymphocyte receptor bearing cells with an added caspase suicide gene represents a recent modification to the technique; if acute GVHD occurs, the administration of rimiducid, a compound which activates the suicide gene, is able to remove the targeted cells (15).…”
Section: Overview On Hematopoietic Stem Cell Transplantation In Primamentioning
Primary immunodeficiencies (PID) are disorders that for the most part result from mutations in genes involved in immune host defense and immunoregulation. These conditions are characterized by various combinations of recurrent infections, autoimmunity, lymphoproliferation, inflammatory manifestations, atopy, and malignancy. Most PID are due to genetic defects that are intrinsic to hematopoietic cells. Therefore, replacement of mutant cells by healthy donor hematopoietic stem cells (HSC) represents a rational therapeutic approach. Full or partial ablation of the recipient's marrow with chemotherapy is often used to allow stable engraftment of donor-derived HSCs, and serotherapy may be added to the conditioning regimen to reduce the risks of graft rejection and graft versus host disease (GVHD). Initially, hematopoietic stem cell transplantation (HSCT) was attempted in patients with severe combined immunodeficiency (SCID) as the only available curative treatment. It was a challenging procedure, associated with elevated rates of morbidity and mortality. Overtime, outcome of HSCT for PID has significantly improved due to availability of high-resolution HLA typing, increased use of alternative donors and new stem cell sources, development of less toxic, reduced-intensity conditioning (RIC) regimens, and cellular engineering techniques for graft manipulation. Early identification of infants affected by SCID, prior to infectious complication, through newborn screening (NBS) programs and prompt genetic diagnosis with Next Generation Sequencing (NGS) techniques, have also ameliorated the outcome of HSCT. In addition, HSCT has been applied to treat a broader range of PID, including disorders of immune dysregulation. Yet, the broad spectrum of clinical and immunological phenotypes associated with PID makes it difficult to define a universal transplant regimen. As such, integration of knowledge between immunologists and transplant specialists is necessary for the development of innovative transplant protocols and to monitor their results during follow-up. Despite the improved outcome observed after HSCT, patients with severe forms of PID still face significant challenges of short and long-term transplant-related complications. To address this issue, novel HSCT strategies are being implemented aiming to improve both survival and long-term quality of life. This article will discuss the current status and latest developments in HSCT for PID, and present data regarding approach and outcome of HSCT in recently described PID, including disorders associated with immune dysregulation.
Summary
The first umbilical cord blood (UCB) transplantation was performed 30 years ago. UCB transplantation (UCBT) is now widely used in children with malignant and non‐malignant disorders who lack a matched family donor. UCBT affords a lower incidence of graft‐versus‐host disease compared to alternative stem cell sources, but also presents a slower immune recovery and a high risk of infections if serotherapy is not omitted or targeted within the conditioning regimen. The selection of UCB units with high cell content and good human leucocyte antigen match is essential to improve the outcome. Techniques, such as double UCBT, ex vivo stem cell expansion and intra‐bone injection of UCB, have improved cord blood engraftment, but clinical benefit remains to be demonstrated. Cell therapies derived from UCB are under evaluation as potential novel strategies to reduce relapse and viral infections following transplantation. In recent years, improvements within haploidentical transplantation have reduced the overall use of UCBT as an alternative stem cell source; however, each may have its relative merits and disadvantages and tailored use of these alternative stem cell sources may be the optimal approach.
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