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

The innate immune system of severe combined immunodeficient (SCID) mice rep resents 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 wi th human peripheral blood leucocytes (Hu-PBL) because of their reduced natu ral killer cell and macrophage activity next to defective T and B cell func tions. We investigated effects of TM-beta 1, a rat monoclonal antibody reco gnizing the mouse IL-2 receptor beta-chain, on Hu-PBL survival and function in NOD-SCID and SCID mice. Relative to untreated littermates, TM-beta 1 im proved Hu-PBL survival in SCID and NOD-SCID mice. Moreover, TM-beta 1-pretr eated NOD-SCID mice displayed significantly better Hu-PBL survival and tiss ue distribution than TM-beta 1-pretreated SCID mice. Irradiation of NOD-SCI D mice further enhanced the effects of TM-beta 1. However, these animals di ed within 3 weeks post-grafting due to graft-versus-host disease. Secondary immune responses were evaluated with Hu-PBL from a donor immune to hepatit is B surface antigen (HBsAg). In TM-beta 1-pretreated NOD-SCID mice, human HBsAg-specific memory B cells produced high titres of anti-HBsAg immunoglob ulin irrespective of the administration of a secondary antigen booster dose . This contrasts with secondary immune responses in TM-beta 1-pretreated SC ID mice where high titred antigen-specific immunoglobulins were produced wh en the appropriate antigen booster was given. In conclusion, reducing the f unction of the innate immune system in immunodeficient mice improves surviv al of the human graft and can result in an activation of the memory B cells without the need for recall antigen exposure.