Advances in Human Immune System Mouse Models for Studying Human Hematopoiesis and Cancer Immunotherapy

Abstract

Immunotherapy has established itself as a promising tool for cancer treatment. There are many challenges that remain including lack of targets and some patients across various cancers who have not shown robust clinical response. One of the major problems that have hindered the progress in the field is the dearth of appropriate mouse models that can reliably recapitulate the complexity of human immune-microenvironment as well as the malignancy itself. Immunodeficient mice reconstituted with human immune cells offer a unique opportunity to comprehensively evaluate immunotherapeutic strategies. These immunosuppressed and genetically modified mice, with some overexpressing human growth factors, have improved human hematopoietic engraftment as well as created more functional immune cell development in primary and secondary lymphoid tissues in these mice. In addition, several new approaches to modify or to add human niche elements to further humanize these immunodeficient mice have allowed a more precise characterization of human hematopoiesis. These important refinements have opened the possibility to evaluate not only human immune responses to different tumor cells but also to investigate how malignant cells interact with their niche and most importantly to test immunotherapies in a more preclinically relevant setting, which can ultimately lead to better success of these drugs in clinical trials.

Impact of Impaired Cholesterol Homeostasis on Neutrophils in Atherosclerosis

“…There are significant differences between the hematological systems of mice and humans at both the levels of hematopoietic stem cells, mature leukocytes and the cross talk between various elements of the immune system. 69 As new murine models of hematopoiesis that more closely emulate humans continue to emerge, 70 hopefully too will our understanding of the relationship between cholesterol and neutrophils in preclinical models of atherosclerosis.…”

HTLV-1 Infection and Pathogenesis: New Insights from Cellular and Animal Models

“…These mice allow the engraftment of human cells. By introducing additional genetic mutations, several other types of SCID immunocompromised mouse strains become available, i.e., NOD-SCID mice, in which SCID mutation is present in a non-obese diabetic (NOD) genetic background mouse that shows NK cell dysfunction, low cytokine production, and T- and B-cell deregulation; NSG and NOG mice, in which different mutations in the interleukin-2 receptor common subunit γ (IL2R-γC) leading to a complete loss of T, B, and NK cells, are introduced into the NOD/SCID background; and BALB/c mice deficient in IL2R-γC and the recombinase-activating gene 2 (Rag2) (BRG), which are impaired in T- and B-cell differentiation and have high levels of NK-cell activity [ 163 ].…”

Immune Prophylaxis and Therapy for Human Cytomegalovirus Infection

“…For example, generating these models is labor intensive and requires the application of advanced surgical skills. In addition, not all elements of HIS are equally expressed, with monocytes and macrophages lagging to a large extent [42]. Given the role that cells of macrophage lineage play in latency and, especially, reactivation of HCMV, this limitation can contribute to the reduction in viral load and spread seen in the humanized mouse compared to the human host [41].…”