Part of the book: New Advances in Stem Cell Transplantation
Remarkable progress in the experimental and clinical applications of cell-based therapies has identified stem cells and their derived products as potential candidates for regenerative therapies for many disorders. The use of autologous stem cells as source for regenerative therapeutic products is strongly limited by their low availability. Therefore, the future applications of in vitro pharmed therapeutic cell products will most likely occur in an allogeneic manner. However, the high variability of the human leukocyte antigen (HLA) represents a major obstacle to the application of off-the-shelf products. We have developed a strategy to decrease the immunogenicity of in vitro generated cell products by silencing HLA expression using RNAi. HLA expression was permanently silenced in CD34+ hematopoietic stem and progenitor cells and induced the pluripotent stem cells to generate HLA-universal cells sources, which were then used for the differentiation of low immunogenic cell products. In this chapter, we will provide an overview about an RNAi-based strategy to reduce the immunogenicity of cell-based therapies, and in particular in the generation of HLA-universal platelets and tissues.
Part of the book: RNA Interference
Drug Hypersensitivity reactions can be distinguished in adverse drug events and adverse drug reactions. They represent a major problem in the medical scheme, since they are often underestimated. Pharmacogenetic analysis demonstrated significant associations between emerging hypersensitivity reactions and distinct genes of the HLA complex. HLA-mediated hypersensitivity reactions particularly affect skin and liver, however, impairment of the bone marrow and kidney function could also be observed. These life threatening medical conditions can be attributed to the activation of autologous drug-specific T-cells. Severe drug hypersensitivity reactions that resemble acute GvHD are linked to certain specific HLA alleles. The most common hypersensitivity reactions occur after the treatment of HLA-B*57:01+ HIV patients with abacavir and HLA-A*31:01+ or B*15:02+ epileptic patients with carbamazepine (CBZ).
Part of the book: Physiology and Pathology of Immunology
Positive and negative selection in the thymus relies on T-cell receptor recognition of peptides presented by HLA molecules and determines the repertoire of T cells. Immune competent T-lymphocytes target cells display nonself or pathogenic peptides in complex with their cognate HLA molecule. A peptide passes several selection processes before being presented in the peptide binding groove of an HLA molecule; here the sequence of the HLA molecule’s heavy chain determines the mode of peptide recruitment. During inflammatory processes, the presentable peptide repertoire is obviously altered compared to the healthy state, while the peptide loading pathway undergoes modifications as well. The presented peptides dictate the fate of the HLA expressing cell through their (1) sequence, (2) topology, (3) origin (self/nonself). Therefore, the knowledge about peptide competition and presentation in the context of alloreactivity, infection or pathogenic invasion is of enormous significance. Since in adoptive cellular therapies transferred cells should exclusively target peptide-HLA complexes they are primed for, one of the most crucial questions remains at what stage of viral infection viral peptides are presented preferentially over self-peptides. The systematic analyzation of peptide profiles under healthy or pathogenic conditions is the key to immunological success in terms of personalized therapeutics.
Part of the book: Polypeptide
HLA molecules scan the intracellular proteome and present self- or non-self-peptides to immune effector cells. HLA-Ia (HLA-A, HLA-B and HLA-C) are the most polymorphic genes, resulting in various numbers of allelic variants expressed on the surface of almost all nucleated cells. In contrast to HLA-Ia molecules that activate the immune system during pathogenic invasion, the marginal polymorphic HLA-Ib molecules (HLA-E, HLA-F and HLA-G) are upregulated during pathogenic episodes and mediate immune tolerance. A fine tuning between downregulation of HLA-Ia and upregulation of HLA-Ib can be observed through immunological episodes that require to remain unrecognized by immune effector cells. While HLA-Ia molecules collaborate by presenting a wide range of peptides, every HLA-Ib molecule is highly specialized in its protective immune function and seems to be restricted in the presentation of peptides. Additionally, Ia molecules are expressed ubiquitously while the expression of HLA-Ib molecules is strictly restricted to certain tissues and occurs instantly on demand of the cells/tissue that attempt to be hidden from the immune system. The more knowledge becomes available for the function of HLA-Ib molecules; the question emerges if the molecular typing of HLA-Ib molecules would be reasonable to take a decision post treatment for personalized cellular therapies.
Part of the book: Immunogenetics