The findings are in accord with previous research among other chronically ill populations in suggesting an association between stress, coping, and maternal adjustment. Within the limitations of the study, the data were interpreted to support the utility of theoretical models in identifying areas in need of intervention across chronic illness groups.

One of the major limitations of unrelated umbilical cord blood transplantation (UCBT) is the lack of donor cells available for post-transplant donor leukocyte infusions (DLI) to boost immunity or induce GVL. Starting from ~5% fraction of a UCB graft we report the feasibility and biological characteristics of ex vivo expansion of frozen/thawed cord blood T cells by anti-CD3 and anti-CD28 antibody-coated Dynal beads in the presence of IL-2. We postulated that while undergoing expansion, CB T cells may mature towards a Th1/Tc1 phenotype and acquire the potential for cytotoxicity. While an almost 2 log expansion also led to the acquisition of IL-12Rα and increase in Th1 characteristics, post-expansion lymphocytes produced less IFNγ, TNFα, Granzyme B, stored almost no perforin, and lacked cytotoxicity against allogeneic targets. Collectively, these suggest relative safety from acute/hyperacute GVHD. CD8+ T cells expanded preferentially while a higher rate of apoptosis among CD4+ T cells promoted an inverted CD4/CD8 ratio. Most expanded T cells retained expression of CD27, CD28, L-selectin, however, the majority down regulated CCR-7. In sum, CB T cell proliferation sustained by CD3/CD28 costimulatory beads and IL-2 can lead to clinically relevant doses of DLI from a very small fraction of the UCB graft, although future strategies to reduce apoptosis may enhance their clinical potential.

Donor leukocyte infusions (DLI) in the allogeneic hematopoietic transplant setting can provide a clinically relevant boost of immunity to reduce opportunistic infections and to increase graft-versus-leukemia activity. Despite significant advances in applicability, DLI has not been available for single-unit recipients of unrelated cord blood transplant. Ex vivo expansion of cord blood T cells can be achieved with interleukin (IL)-2 and CD3/CD28 costimulatory beads. However, significant apoptosis occurs in proliferating T cells, diminishing the yield and skewing the CD4/CD8 ratio in the T-cell population, jeopardizing the potential efficacy of DLI. In this study, we show that interleukin (IL)-7 not only reduces apoptosis of activated T lymphocytes and enhances their proliferation but also promotes functional maturation, leading to secretion of IFN-γ and other key cytokines. Recognizing that infused T lymphocytes will need to meet microbial antigens in secondary lymphoid organs to generate effectors, we also show that expansion with IL-7 promotes the preservation of a polyclonal broad T-cell receptor repertoire and a surface phenotype that favors lymph node homing. Expanded lymphocytes lack alloreactivity against recipient and other allogeneic cells, indicating a favorable safety profile from graft-versus-host disease. Nevertheless, expanded T cells can be primed subsequently against lymphoid and myeloid leukemia cells to generate tumor-specific cytotoxic T cells. Taken together, our findings offer a major step in fulfilling critical numerical and biological requirements to quickly generate a DLI product ex vivo using a negligible fraction of a cord blood graft that provides a flexible adoptive immunotherapy platform for both children and adults. Cancer Res; 70(13); 5249-58. ©2010 AACR.

Elderly individuals have increased morbidity and mortality associated with infectious diseases due in part to the progressive age-associated decline in immune function. Despite this, the old mouse model of Mycobacterium tuberculosis infection has revealed a CD8-and gamma interferon (IFN-␥)-dependent early resistance to infection. In this study, we investigated the mechanism by which CD8 T cells from old mice contributed to the early immune response to M. tuberculosis. Following a low-dose aerosol infection with M. tuberculosis, CD8 T cells were identified as being a dominant source of IFN-␥ expression in the lungs of old mice early after infection, before the typical onset of antigen-specific immunity. In addition, M. tuberculosis-induced IFN-␥ production by CD8 T cells isolated from naïve old mice was major histocompatibility complex class I independent but was dependent on interleukin-12p70, confirming an innate role of CD8 T cells during M. tuberculosis infection. Moreover, the ability of CD8 T cells from old mice to produce increased innate IFN-␥ levels in response to M. tuberculosis infection was defined as a unique function of CD8 T cells from old mice and not the aged lung environment. Finally, we have identified increased expression of SET as being one possible mechanism by which CD8 T cells from old mice produce enhanced levels of IFN-␥. Additional characterizations of the signaling events that lead to enhanced innate IFN-␥ production by CD8 T cells in old mice may lead to novel strategies to further enhance or perpetuate beneficial immune responses in the elderly.