Table 1.

Pitfalls of humanized models and the means to compensate them.

Problem definition	Impact on progress in research	Ways to overcome limitations	Ref.
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]
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]
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.
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]
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]
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]
Immunoglobulin switching	Inability to mimic humoral responses	Development of human IL-6 producing mice, introduction of additional cytokine modification	[38, 54]
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]
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]