Cord blood in regenerative medicine: do we need immune suppression?

Cord blood is currently used as an alternative to bone marrow as a source of stem cells for hematopoietic reconstitution after ablation. It is also under intense preclinical investigation for a variety of indications ranging from stroke, to limb ischemia, to myocardial regeneration. A major drawback in the current use of cord blood is that substantial morbidity and mortality are associated with pre-transplant ablation of the recipient hematopoietic system. Here we raise the possibility that due to unique immunological properties of both the stem cell and non-stem cell components of cord blood, it may be possible to utilize allogeneic cells for regenerative applications without needing to fully compromise the recipient immune system. Issues raised will include: graft versus host potential, the immunogeneicity of the cord blood graft, and the parallels between cord blood transplantation and fetal to maternal trafficking. The previous use of unmatched cord blood in absence of any immune ablation, as well as potential steps for widespread clinical implementation of allogeneic cord blood grafts will also be discussed

Therapeutic use of Aldara™ in chronic myeloid leukemia

The potent clinical responses seen in patients with chronic myeloid leukemia (CML) after administration of donor-specific lymphocytes, as well as the correlation between the presence of antigen specific T cells and prolonged remission in these patients, suggests a role for the immunological control of CML. Here we propose Aldara™, a clinically used formulation of imiquimod, as an agent for augmenting immune responses to CML antigens. Our proposition is based upon 3 tenets: 1) Endogenous dendritic cells (DC) of CML patients, which are known to be derived from the malignant clone, express and present various leukemic antigens; 2) CML-antigen reactive T cell clones exist in the patient but in many situations are ineffectively stimulated to cause significant hematological responses; and 3) Antigen presentation by mature, activated DC, which endogenously express CML-antigens may endow the pre-existing ineffective T cell responses with ability to control CML progression. The practical use of Aldara™ as a localized activator of DC in the context of present day leukemic therapeutics, as well as various properties of this unique immune modulator will be discussed

Allogeneic endometrial regenerative cells: An "Off the shelf solution" for critical limb ischemia?

Critical limb ischemia (CLI) is an advanced form of peripheral artery disease which is responsible for approximately 100,000 amputations per year in the US. Trials to date have reported clinical improvement and reduced need for amputation in CLI patients receiving autologous bone marrow or mobilized peripheral blood stem cells for stimulation of angiogenesis. While such treatments are currently entering Phase III trials, practical and scientific pitfalls will limit widespread implementation if efficacy is proven. Hurdles to be overcome include: a) reduced angiogenic potential of autologous cells in aged patients with cardiovascular risk factors; b) invasiveness/adverse effects of bone marrow extraction and G-CSF mobilization, respectively; and c) need for on-site cellular manipulation. The Endometrial Regenerative Cell (ERC) is a mesenchymal-like stem cell derived from the menstrual blood that is believed to be associated with endometrial angiogenesis. We discuss the possibility of using allogeneic ERCs as an "off the shelf" treatment for CLI based on the following properties: a) High levels of growth factors and matrix metalloprotease production; b) Ability to inhibits inflammatory responses and lack of immunogenicity; and c) Expandability to great quantities without loss of differentiation ability or karyotypic abnormalities

Autologous stromal vascular fraction therapy for rheumatoid arthritis: rationale and clinical safety

Advancements in rheumatoid arthritis (RA) treatment protocols and introduction of targeted biological therapies have markedly improved patient outcomes, despite this, up to 50% of patients still fail to achieve a significant clinical response. In veterinary medicine, stem cell therapy in the form of autologous stromal vascular fraction (SVF) is an accepted therapeutic modality for degenerative conditions with 80% improvement and no serious treatment associated adverse events reported. Clinical translation of SVF therapy relies on confirmation of veterinary findings in targeted patient populations. Here we describe the rationale and preclinical data supporting the use of autologous SVF in treatment of RA, as well as provide 1, 3, 6, and 13 month safety outcomes in 13 RA patients treated with this approach

Dendritic Cells and Immunoregulation in the Pathogenesis and Prevention of Type 1 Diabetes

Dendritic cells govern the outcome of an immune response toward either tolerance or autoimmunity. Recent evidence has demonstrated that central tolerance is associated with relatively immature dendritic cells or quiescent mature dendritic cells that present self-antigens to autoreactive T cells, thereby silencing their autoreactive potential and/or activating regulatory T cells. Conversely, activated mature dendritic cells that have been instructed to become potent T cell stimulators by adjuvants or pathogens are capable of converting tolerance to immune activation. In combination with genetic and environmental influences, such mature dendritic cells are capable of orchestrating autoimmune responses. To explore the function of dendritic cells in type 1 diabetes, the authors evaluated peripheral dendritic cells from both patients with type 1 diabetes and the nonobese diabetic (NOD) mouse model that shares a pathologically analogous disease process. Dendritic cells in NOD mice are phenotypically comparable to dendritic cells from autoimmune-resistant controls with respect to expression of differentiation molecules. However, in response to maturation stimuli, such cells confer heightened activation of T cells and excessive production of pro-inflammatory cytokines. These findings highlight a putative contribution of unabated dendritic cell activation to the loss of self-tolerance and to chronic, self- directed responses that define type 1 diabetes. Moreover, effective manipulation of dendritic cell activation state pro- vides a promising avenue for regulating autoimmunity. Using a novel self-derived peptide that programs dendritic cell maturation and activation from monocytic precursors, the authors demonstrated suppression of autoreactivity in the NOD mouse model of type 1 diabetes. Collectively, these data are consistent with a model in which dendritic cells at different maturation and activation states regulate peripheral tolerance vs. autoimmunity