Combined deficiency in CD44 and Fas leads to exacerbation of lymphoproliferative and autoimmune disease.

Patients with mutations in Fas develop autoimmune lymphoproliferative disease (ALPS), while their family members with similar mutations are often normal, thereby suggesting that additional factors may play a role in the development of ALPS. In the current study, we tested the role of CD44 in the development of lymphoproliferative disease by generating CD44(-/-)/Fas(-/-) mice, which failed to express CD44 and Fas, and compared them to CD44(+/+)/Fas(-/-) mice that expressed CD44, but not Fas. The results showed that CD44(-/-)/Fas(-/-) mice developed a more severe lymphoproliferative and autoimmune disease when compared to CD44(+/+)/Fas(-/-) mice. This was indicated by increased numbers of cells in their lymph nodes, and a greater proportion of B220(+)CD4(-)CD8(-) (double-negative) T cells as well as antibodies against single-stranded DNA and chromatin. The heightened severity of lymphoproliferative disease seen in CD44(-/-)/Fas(-/-) mice correlated with increased resistance of T cells, but not B cells, to undergo activation-induced cell death (AICD). The current study suggests that deficiency in CD44 in combination with a defect in one of the molecules involved in the death receptor family such as Fas can further down-regulate AICD, and exacerbate the lymphoproliferative and autoimmune disease.

Influence of adjuvants in inducing immune responses to different epitopes included in a multiepitope, multivalent, multistage Plasmodium falciparum candidate vaccine (FALVAC-1) in outbred mice.

FALVAC-1, a vaccine against Plasmodium falciparum was developed by joining 21 epitopes from P. falciparum vaccine antigens and an universal T helper epitope from tetanus toxoid. Since adjuvants influence different aspects of immune responses, in this study we investigated the effect of four adjuvants aluminum hydroxide (alum), nonionic copolymer adjuvant P1005 (water-in-oil emulsion), CpG oligodeoxynucleotides (ODN), and QS-21 in eliciting immune responses in outbred mice. QS-21 and copolymer adjuvants were the best formulations in inducing higher and long-lasting antibody titers to the whole vaccine compared to alum and CpG. QS-21 was the only adjuvant to elicit predominantly IgG2a response and antibodies reactive with all epitopes incorporated in the vaccine construct. Vaccine elicited antibodies recognized sporozoites and asexual blood-stage parasites. FALVAC-1 immunized mice induced lymphoproliferative and IFN-gamma response to the vaccine. QS-21 and CpG adjuvants were able to elicit T proliferative responses to 20 of the 22 epitopes in the vaccine. In conclusion, this study demonstrated that with suitable adjuvant such as QS-21, it is possible to elicit immune responses to most of the epitopes included in the FALVAC-1 vaccine.