Maitta Robert W, Datta Kausik, Pirofski Liise-Anne
Departments of Microbiology and Immunology, Room 709 Forchheimer Bldg, Albert Einstein College of Medicine, Bronx, NY 10461, USA.
Vaccine. 2004 Sep 28;22(29-30):4062-8. doi: 10.1016/j.vaccine.2004.03.060.
The efficacy of antibody mediated immunity against Cryptococcus neoformans has not been established experimentally for human antibodies. Our group has previously shown that immunization with a conjugate consisting of a peptide mimotope of the C. neoformans capsular polysaccharide glucuronoxylomannan (GXM), P13, and diphtheria toxoid (P13-DT) prolonged survival of transgenic mice with human immunoglobulin loci, XenoMouse mice, which were challenged with a lethal dose of C. neoformans. In the study reported herein, we determined the efficacy of human antibodies in the sera of immunized XenoMouse mice against C. neoformans in passive transfer experiments in naïve BALB/c mice. Survival studies were performed with sera from XenoMouse mice expressing human IgG2/kappa (G2/k mice) or IgG4/kappa (G4/k mice) that had been immunized with P13-tetanus toxoid (TT)/Alhydrogel with or without CpG, and G2/k mice that had been immunized with P13-DT/Alhydrogel/CpG or Alhydrogel/CpG, obtained on day 7 (early sera) and days 30 or 35-59 (late sera) after primary immunization. Compared to mice receiving sera from G2/k-PBS-treated mice, the survival of naïve mice was prolonged by both early and late sera from G2/k-P13-DT/Alhydrogel/CpG-immunized mice, but only late sera from G2/k-P13-TT/Alhydrogel/CpG-immunized mice. Late, but not early sera from G2/k-Alhydrogel/CpG-immunized mice also prolonged survival. For all sera, prolongation of survival was associated with GXM-specific serum IgM. Sera from G2/k mice that received P13-TT without CpG, and all groups of G4/k mice had low to undetectable levels of antibody to GXM and were not protective. Our findings suggest that GXM-specific human IgM may be a functional mediator of protection against C. neoformans.
针对新型隐球菌的抗体介导免疫对人类抗体的功效尚未通过实验确定。我们小组先前已表明，用由新型隐球菌荚膜多糖葡糖醛酸木聚糖甘露聚糖（GXM）的肽模拟表位P13与白喉类毒素（P13-DT）组成的偶联物免疫，可延长携带人免疫球蛋白基因座的转基因小鼠（XenoMouse小鼠）的存活时间，这些小鼠受到致死剂量的新型隐球菌攻击。在本文报道的研究中，我们在未免疫的BALB/c小鼠的被动转移实验中，确定了免疫的XenoMouse小鼠血清中的人抗体对新型隐球菌的功效。用表达人IgG2/κ（G2/κ小鼠）或IgG4/κ（G4/κ小鼠）的XenoMouse小鼠的血清进行存活研究，这些小鼠用P13-破伤风类毒素（TT）/氢氧化铝佐剂（Alhydrogel）免疫，添加或不添加CpG，以及用P13-DT/Alhydrogel/CpG或Alhydrogel/CpG免疫的G2/κ小鼠，在初次免疫后第7天（早期血清）和第30天或第35 - 59天（晚期血清）获取血清。与接受来自G2/κ - PBS处理小鼠血清的小鼠相比，未免疫小鼠的存活时间因来自G2/κ - P13-DT/Alhydrogel/CpG免疫小鼠的早期和晚期血清而延长，但仅因来自G2/κ - P13-TT/Alhydrogel/CpG免疫小鼠的晚期血清而延长。来自G2/κ - Alhydrogel/CpG免疫小鼠的晚期而非早期血清也延长了存活时间。对于所有血清，存活时间的延长与GXM特异性血清IgM相关。接受不含CpG的P13-TT的G2/κ小鼠的血清，以及所有组的G4/κ小鼠对GXM的抗体水平低至无法检测，且无保护作用。我们的研究结果表明，GXM特异性人IgM可能是针对新型隐球菌的保护性功能性介质。
