Mouse strain and conditioning regimen determine survival and function of human leucocytes in immunodeficient mice

Abstract

SUMMARYThe innate immune system of severe combined immunodeficient (SCID) mice represents an important barrier to the successful engraftment of human cells. Different genetic and pharmacological strategies improve the graft survival. Non-obese diabetic (NOD)-SCID mice are better hosts for reconstitution with human peripheral blood leucocytes (Hu-PBL) because of their reduced natural killer cell and macrophage activity next to defective T and B cell functions. We investigated effects of TM-b1, a rat monoclonal antibody recognizing the mouse IL-2 receptor b-chain, on Hu-PBL survival and function in NOD-SCID and SCID mice. Relative to untreated littermates, TM-b1 improved Hu-PBL survival in SCID and NOD-SCID mice. Moreover, TM-b1-pretreated NOD-SCID mice displayed significantly better Hu-PBL survival and tissue distribution than TM-b1-pretreated SCID mice. Irradiation of NOD-SCID mice further enhanced the effects of TM-b1. However, these animals died within 3 weeks postgrafting due to graft-versus-host disease. Secondary immune responses were evaluated with Hu-PBL from a donor immune to hepatitis B surface antigen (HBsAg). In TM-b1-pretreated NOD-SCID mice, human HBsAg-specific memory B cells produced high titres of anti-HBsAg immunoglobulin irrespective of the administration of a secondary antigen booster dose. This contrasts with secondary immune responses in TM-b1-pretreated SCID mice where high titred antigen-specific immunoglobulins were produced when the appropriate antigen booster was given. In conclusion, reducing the function of the innate immune system in immunodeficient mice improves survival of the human graft and can result in an activation of the memory B cells without the need for recall antigen exposure.

Immunoglobulin-Like Transcript 3-Fc Suppresses T-Cell Responses to Allogeneic Human Islet Transplants in hu-NOD/SCID Mice

“…In addition to T-and B-cell deficiency, NOD/SCID mice have functional defects of macrophages and natural killer cells (31)(32)(33)(34) and high rates of human lymphocyte engraftment (34), providing a tool for studying human islet allograft rejection and the effect of immunomodulatory agents (25,28,35,36). The rate of T-cell engraftment observed in our study was similar to that described by other authors studying the same strain of mice (34).…”

Factors affecting human T cell engraftment, trafficking, and associated xenogeneic graft-vs-host disease in NOD/SCID β2mnull mice

“…[45,[51][52][53][54] The mechanism/s by which pre-transplant irradiation of NOD/SCID-β2m null recipients increases the incidence of lethal X-GVHD induced by huT cells remains unknown. One possibility is that TBI provides additional immunosuppression, thereby permitting increased huT cell engraftment and subsequent development of lethal X-GVHD [23]. Consistent with this hypothesis, we found significantly increased huT cell engraftment in the peripheral blood of NOD/SCID-β2m null mice after increasing the TBI dose from 250 cGy to 300 cGy and decreasing the time between irradiation and huT cell injection from 24 h to <6 h. A second possibility is that the pre-transplant irradiation prompts massive cytokine induction, also known as the "cytokine storm", which promotes huT cell engraftment, activation and development of lethal X-GVHD [49].…”

“…Initial experiments using SCID mice, which lack functional T and B-cells, demonstrated that anywhere from 1% to 20% of unconditioned SCID mice could develop xenogeneic GVHD (X-GVHD) following intraperitoneal (i.p.) injection of extremely high numbers (50-100 × 10 6 ) of human peripheral blood mononuclear cells (huPBMCs) [14,[17][18][19][20][21][22][23]. Nonobese diabetic (NOD)/SCID mice exhibit reduced NK activity, macrophage function and serum hemolytic complement activity in addition to the deficit in mature T and B cells [24,25].…”

“…Nonobese diabetic (NOD)/SCID mice exhibit reduced NK activity, macrophage function and serum hemolytic complement activity in addition to the deficit in mature T and B cells [24,25]. Although increased huT cell engraftment levels and X-GVHD have been reported for NOD/SCID mice, these mice are still constrained by the presence of residual NK cell activity and poor human CD4 + T cell engraftment [23,24,[26][27][28][29][30]. Recently, this residual NK cell activity was virtually eliminated by backcrossing the β 2 -microglobulinnull (β2m null ) allele onto the NOD/SCID background [31].…”

“…pretransplant conditioning with sublethal irradiation [19,23,26,[32][33][34][35][36][37][38][39][40], (ii.) targeted reduction of murine natural killer (NK) cell activity with antibodies directed towards specific cell membrane markers (anti-asialo-GM1 [19,[33][34][35] or anti-CD122 [23,36,39]), (iii.) targeted reduction of murine macrophages with clodronate-containing liposomes [37], (iv.)…”