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Problem definition | Impact on progress in research | Ways to overcome limitations | Ref. |
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The artificial condition of housing | Increased susceptibility of the animals to infection, decreased immunity, | Creating a more realistic environment for housing | [2, 4, 7, 12] |
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Clinical relevance of septic model in general | Separation of the research outcome from clinical reality. | Developing more clinically relevant model by introducing fluid resuscitation and antibiotics, comparisons between humanized and non-humanized animals. | [2, 8, 10] |
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Homogeneity of animals | Decrease robustness of the findings. | Increasing diversity, developing models with different strains, engaging in cross-species research, grafting with different stem cells. | |
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Preservation of mice native immune system | Incomplete or inefficient grafting, GVHD, the emergence of lymphomas | Development of more profoundly immunosuppressed hosts, eradication of the residual immune system, knock-out of SIRP-α. | [13, 16, 17, 19, 24, 28, 30, 34, 45–47] |
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Lack of supportive human cytokine environment | Inefficient grafting, inefficient cytokine network and immune system regulation | Supplementation of human cytokines via various means | [31, 37, 48–52] |
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Poor recovery of certain leukocyte population | Incomplete restoration of the immune system, ineffective and clinically irrelevant responses | Introduction of HIS, BLT, MITGR models, supplementation of human cytokines via genetic engineering, | [10, 16, 19, 22, 24, 25, 33, 34, 36, 44, 53] |
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Immunoglobulin switching | Inability to mimic humoral responses | Development of human IL-6 producing mice, introduction of additional cytokine modification | [38, 54] |
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Functional immaturity of human leukocytes | The inappropriate response, difficulties in translating | Supplementation of adequate cytokine environment, ex vivo cell maturation, and supplementation | [35, 51, 55] |
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Poor inter-organ communication | Difficulty mimicking complex interaction between organs in sepsis | Additional transplantation to better mimic inter-organ interaction in the autologous/allogeneic system, the introduction of human intestinal flora | [35, 54–57] |
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