Enhanced Immune Reconstitution by Sex Steroid Ablation following Allogeneic Hemopoietic Stem Cell Transplantation

Department of Pathology and Immunology, Central and Eastern Clinical School, Monash University, Melbourne, Australia.
The Journal of Immunology (Impact Factor: 4.92). 07/2007; 178(11):7473-84. DOI: 10.4049/jimmunol.178.11.7473
Source: PubMed


Delayed immune reconstitution in adult recipients of allogeneic hemopoietic stem cell transplantations (HSCT) is related to age-induced thymic atrophy. Overcoming this paucity of T cell function is a major goal of clinical research but in the context of allogeneic transplants, any strategy must not exacerbate graft-vs-host disease (GVHD) yet ideally retain graft-vs-tumor (GVT) effects. We have shown sex steroid ablation reverses thymic atrophy and enhances T cell recovery in aged animals and in congenic bone marrow (BM) transplant but the latter does not have the complications of allogeneic T cell reactivity. We have examined whether sex steroid ablation promoted hemopoietic and T cell recovery following allogeneic HSCT and whether this benefit was negated by enhanced GVHD. BM and thymic cell numbers were significantly increased at 14 and 28 days after HSCT in castrated mice compared with sham-castrated controls. In the thymus, the numbers of donor-derived thymocytes and dendritic cells were significantly increased after HSCT and castration; donor-derived BM precursors and developing B cells were also significantly increased. Importantly, despite restoring T cell function, sex steroid inhibition did not exacerbate the development of GVHD or ameliorate GVT activity. Finally, IL-7 treatment in combination with castration had an additive effect on thymic cellularity following HSCT. These results indicate that sex steroid ablation can profoundly enhance thymic and hemopoietic recovery following allogeneic HSCT without increasing GVHD and maintaining GVT.

Download full-text


Available from: Ann P Chidgey, Jul 10, 2014
  • Source
    • "The size of the naïve T cell compartments are regulated by the pace of generation naïve T cells in the thymus, the lifespan of the naïve T cells and whatever homeostatic turnover of T cells occurs in the periphery . Starting in adolescence, there is a pronounced onset of thymic involution that is linked to the appearance of sex hormones and reinforced by decreases in growth hormones [24] [25] [26] [27]. Progressive thymic involution with age causes a steady decline in new thymic emigrants, which drop approximately 10-fold compared to that in pre-adolescent animals over several months and RTE then remain at a stable, low level [22] [28]. "
    [Show abstract] [Hide abstract]
    ABSTRACT: Our recent studies indicate that the longer peripheral persistence of naïve CD4 T cells that occurs with age is necessary for the development of the key aging defects that lead to compromised responses to vaccination and to new pathogens or new strains of circulating infectious agents. This longer persistence is in turn is linked to the decrease in development of new thymic emigrants and thymic involution that occur at adolescence. Therefore the process of development of naïve CD4 aging defects, is closely tied to the homeostasis of T cells and the shifts that occur in their homeostasis with age. Here we review this connection between age-related changes in T cell homeostasis and the development of T cell defects and discuss the implication for approaches to better vaccinating the elderly.
    Full-text · Article · May 2012 · Seminars in Immunology
  • Source
    • "The size of this gland reduces from 200 to 250 grams at birth and then shrinks to around three grams by age 60. Thymic factors are helpful in restoring the immune systems of children born without them as well as rejuvenating the poorly functioning immune systems of the elderly (Goldberg et al., 2007). "
    [Show abstract] [Hide abstract]
    ABSTRACT: The aim of this article was to review the factors that influence the aging, relationship of aging with the biological rhythms and new technologies as well as the main theories to explain the aging, and to analysis the causes of aging. The theories to explain the aging could be put into two groups: those based on a program that controlled the regression of the organism and those that postulated that the deterioration was due to mutations. It was concluded that aging was a multifactorial process. Genetic factors indicated the maximum longevity of the individual and environmental factors responsible for the real longevity of the individual. It would be necessary to guarantee from early age the conservation of a natural life rhythm.
    Full-text · Article · Nov 2010 · Brazilian Archives of Biology and Technology
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Hematopoietic stem cell transplantation (HSCT) is associated with a period of immune incompetence that particularly affects the T cell lineage. Strategies to enhance T cell reconstitution could significantly improve the survival of HSCT recipients by decreasing the incidence of fatal infectious complications and by enhancing graft-versus-tumor activity. In recent years, a variety of promising strategies have been established in preclinical models to improve T cell recovery in particular after allogeneic T cell-depleted HSCT, without aggravating graft-versus-host disease while preserving or even improving graft-versus-tumor activity. These therapies include treatment with keratinocyte growth factor (KGF), growth hormone (GH), LHRH agonists, interleukin 7 (IL-7) and interleukin 15 (IL-15). Thanks to the establishment of Notch-based culture systems, adoptive cellular therapies with T lineage-committed precursor cells have become feasible, since early T cell progenitors can now easily be generated in vitro in large quantities and have been proven to be very effective in enhancing T cell reconstitution and anti-tumor activity after allogeneic T cell-depleted HSCT. The translation of most of these strategies into clinical trials is likely and in some cases Phase I/II studies are already underway.
    Full-text · Article · Jan 2008 · Blood Cells Molecules and Diseases
Show more