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An Introduction to Bone Marrow Transplantation and Processing
Published in Adrian P. Gee, BONE MARROW PROCESSING and PURGING, 2020
The main areas of development in bone marrow purging are the removal of clonogenic tumor cells from the marrow inoculum of patients with malignancies and the prevention of GvHD by T cell depletion. Neither approach has been perfected. In the last few years, we have seen the application of a whole spectrum of innovative techniques in marrow purging technology. However, improved understanding of the underlying biology surrounding reseeded tumor growth capacity is also needed, in order to define more precisely the place of marrow purging in the treatment of malignant disease. In the area of T cell depletion, evidence is accumulating that the cells responsible for the deleterious effect of GvHD are distinct from cells responsible for preserving a GvL effect and also from those responsible for engraftment.57 Development of techniques for selective T cell depletion are clearly indicated.
Autologous Stem Cell Transplantation in Animal Models of Autoimmune Diseases
Published in Richard K. Burt, Alberto M. Marmont, Stem Cell Therapy for Autoimmune Disease, 2019
Rats with EAE respond to autologous BMT with a rapid regression of the neurological symptoms, but one or more spontaneous relapses occur in 30% of the animals.17 When syngeneic BM instead of autologous BM was used for rescue, the spontaneous relapse rate was the same, suggesting that these relapses are initiated by autoreactive cells that have survived the conditioning. This is in accordance with the finding that T cell depletion of autologous or syngeneic BM grafts—which reduced the T cells to 0.1 %—did not diminish the spontaneous relapse rate. Rat bone marrow contains 2-3% T lymphocytes. In these experiments, the number of T lymphocytes (5 × 105) that were reinfused with the unmanipulated bone marrow was in the same range as the estimated number of residual T lymphocytes (106), which explains the futility of T cell depletion in this situation. This does not imply that the number of T lymphocytes returned with the stem cells is irrelevant. On the contrary, the addition of autologous spleen cells containing 3 × 107 T lymphocytes to the BM graft raises the proportion of T cells to over 50% and causes the spontaneous relapse rate to rise to 93%. For comparison: unmanipulated human bone marrow grafts may contain 20-30% T cells and PBSC up to 50%.
AIDS and other acquired immunodeficiencies
Published in Gabriel Virella, Medical Immunology, 2019
John W. Sleasman, Gabriel Virella
CD4 T cell depletion and viral persistence. Ongoing viral replication leads to progressive decline in the numbers and percentages of CD4T cells (Figure 30.6). The principal T-cell population lost is memory CD4 CD45RO+ T cells. Total T-cell depletion is directly correlated with the degree of immunosuppression and risk for AIDS-associated opportunistic infections in infected patients. Several factors account for the depletion of CD4+ T cells. The primary mechanisms are direct cytotoxicity caused by virus replication and cross-linking of CD4 by gp120 that primes T lymphocytes for apoptosis. In spite of the relatively short life of an HIV-infected T cell, persistent replication of competent provirus within latent memory T cells is a major determinant factor in the failure of effective ART to eradicate latent reservoirs in lymphoid tissues and the central nervous system (CNS). Virus can persist because HIV peptides are not expressed on resting cells; thus, they are not CTL or antibody targets. However, even with optimal suppression, latently infected cells are able to produce new virus when activated. Latently infected memory T cells persist for decades, which is why in spite of millions of HIV infections worldwide, cure has been elusive.
Immune checkpoint inhibition in COVID-19: risks and benefits
Published in Expert Opinion on Biological Therapy, 2021
Parmida Sadat Pezeshki, Nima Rezaei
In this article, the three most important immunological manifestations that affect the COVID-19 severity were also explained. Over-expression of both membrane-bound and soluble checkpoint molecules can result in the induction of apoptosis in T-cells and further results in T-cell depletion and lymphopenia. The release of pro-inflammatory cytokines can also result in T-cell depletion. It seems that targeting these three immunological manifestations can resuscitate patients with severe COVID-19 infection. The combinatory administration of ICI with anti-inflammatory agents such as tocilizumab, or along with stimulatory agents for T-cell expansion, such as thymosin or IL-7 [65] might boost the therapeutic outcomes of ICI administration in COVID-19. ICI inhibits the engagement of checkpoint receptors and ligands, thus lowers the T cells death rate, increases the anti-viral T cell function, and subsequently boosts the viral load clearance. While tocilizumab and other anti-inflammatory agents can prevent tissue damage and organ failure by inhibiting cytokines function during CRS.
Malignancy post-hematopoietic stem cell transplant in patients with primary immunodeficiency
Published in Expert Review of Clinical Immunology, 2020
PTLD is the most common MPT in the first year after HCT and solid organ transplantation. Most of these cases are related to impaired immune function during early post-HCT and in most cases, proliferation of EBV infection. CIBMTR and the Fred Hutchinson Cancer Research Center reviewed the largest experience of PTLD in adult and pediatric cohorts which included 26901 allogeneic HCT survivors. This analysis excluded PID (n = 532, 20 PTLD, 8.6%) and Fanconi anemia (n = 328, 1 PTLD, 0.3%). In this study, 127 PTLD were identified and the observed to expected ratio was 29.7% (95% CI, 24.7 to 35.2) compared to age-, sex- and country-adjusted population. The risk factors for PTLD were T-cell depletion (RR 3.1–9.4), use of ATG (RR 3.8), HLA mismatched in the presence of T-cell depletion/ATG (RR 3.8), acute (RR 1.7) and chronic (RR 2.0) GvHD. Lower risks were found for T-cell depletion methods that remove both T and B cells. This analysis demonstrated a multiplicative effect of multiple risk factors on incidence; the incidence was low (0.2%) in 21686 patients with no major risk factors, but increased to 1.1%, 3.6% and 8.1% with 1, 2 or ≥3 major risk factors [45]. Kamani et al. reported 52 post-HSCT malignancies in a large study of 2266 patients with PID giving an overall incidence of 2.3%. The most frequent malignancy was early-onset PTLD in 45 cases, which was associated with T cell depleted grafts [51,52].
Harnessing immunotherapy for pediatric T-cell malignancies
Published in Expert Review of Clinical Immunology, 2020
Caroline Diorio, David T. Teachey
GVHD is a multisystem complication of pediatric HSCT characterized by donor T-cells attacking host tissues[28]. The clinical manifestations of GVHD can be severe, and contribute to morbidity and mortality in post-transplant patients[28]. HSCT is not typically part of upfront therapy for childhood T-ALL, however, it is often recommended in children who relapse or have refractory disease[29]. The pathophysiology of GVHD is complex and mediated by T-cell populations[30]. Using immunotherapies to selectively deplete populations of T-cells in patients may put them at increased risk for GVHD if patients subsequently proceed to transplant. T-cell depletion can lead to graft rejection or GVHD, depending on the population depleted. For example, in grafts that have alpha-beta T-cells depleted, there is a decreased risk of GVHD[30]. In contrast, selectively depleting specific populations of T-cells prior to transplant could change the immune balance in the host and lead to subsequent GVHD. For example, regulatory T-cells (Tregs) play an important role in the prevention of GVHD[31]. CCR4 is highly expressed on Tregs[32]. Mogamulizumab, an anti-CCR4 antibody used in adult patients with peripheral T-cell lymphoma, depletes Tregs. Recent studies have shown an increased risk of GVHD in adult patients who received mogamulizumab prior to transplant[33].