Trichinella spiralis Infection Mitigates Collagen-Induced Arthritis via Programmed Death 1-Mediated Immunomodulation.

Helminth infection induces Th2-biased immune responses and inhibitory/regulatory pathways that minimize excessive inflammation to facilitate the chronic infection of helminth in the host and in the meantime, prevent host hypersensitivity from autoimmune or atopic diseases. However, the detailed molecular mechanisms behind modulation on inflammatory diseases are yet to be clarified. Programmed death 1 (PD-1) is one of the important inhibitory receptors involved in the balance of host immune responses during chronic infection. Here, we used the murine model to examine the role of PD-1 in CD4+ T cells in the effects of Trichinella spiralis infection on collagen-induced arthritis (CIA). Mice infected with T. spiralis demonstrated higher expression of PD-1 in the spleen CD4+ T cells than those without infection. Mice infected with T. spiralis 2 weeks prior to being immunized with type II collagen displayed lower arthritis incidence and significantly attenuated pathology of CIA compared with those of uninfected mice. The therapeutic effect of T. spiralis infection on CIA was reversed by blocking PD-1 with anti-PD-1 antibody, associated with enhanced Th1/Th17 pro-inflammatory responses and reduced Th2 responses. The role of PD-1 in regulating CD4+ T cell differentiation and proliferation during T. spiralis infection was further examined in PD-1 knockout (PD-1-/-) C57BL/6 J mice. Interestingly, T. spiralis-induced alteration of attenuated Th1 and enhanced Th2/regulatory T cell differentiation in wild-type (WT) mice was effectively diminished in PD-1-/- mice characterized by recovered Th1 cytokine levels, reduced levels of Th2 and regulatory cytokines and CD4+CD25+Foxp3+ cells. Moreover, T. spiralis-induced CD4+ T cell proliferation suppression in WT mice was partially restored in PD-1-/- mice. This study introduces the first evidence that PD-1 plays a critical role in helminth infection-attenuated CIA in a mouse model by regulating the CD4+ T cell function, which may provide the new insights into the mechanisms of helminth-induced immunomodulation of host autoimmunity.

Immunomodulation in human and experimental arthritis: including vitamin D, helminths and heat-shock proteins.

Rheumatoid arthritis (RA) is a chronic inflammatory autoimmune disease that is mainly directed to the joints, affecting the synovial membrane, the cartilage and also the bone. This disease affects 1% to 2% of the world population and is associated with significant morbidity and increased mortality. RA experimental models have allowed a great deal of information to be translated to the corresponding human disease. This review summarizes some of the most relevant findings targeting immunomodulation in arthritis. Some general guidelines to choose an adequate experimental model and also our experience with arthritis are supplied.

Taenia crassiceps infection does not influence the development of experimental rheumatoid arthritis.

It was previously reported by our group that infection with Taenia crassiceps reduces incidence and severity of inflammatory and autoimmune experimental diseases like type 1 diabetes and experimental autoimmune encephalomyelitis. In this research, we set out to study whether infection with T. crassiceps would affect the development of experimental rheumatoid arthritis (RA). We found that mice infected with the parasite and induced with experimental RA showed similar clinical scores as the noninfected experimental RA group; systemic cytokines were not affected while anti-CII Abs were higher in the infected group. Histological evaluation showed damage in both infected and noninfected experimental RA-induced groups and although some surface molecules such as PDL-2 and MR which are associated with immunomodulatory mechanisms were upregulated in the infected and RA-induced group as compared to the noninfected RA group, they did not exert any changes in the outcome of experimental RA. Thus, we determined that infection with T. crassiceps does not influence the outcome of experimental RA.

Infection with an intestinal helminth parasite reduces Freund's complete adjuvant-induced monoarthritis in mice.

OBJECTIVE: Assessment of infection with helminth parasites in murine models of disease could identify antiinflammatory mechanisms that translate into treatments for arthritic disease. The aim of this study was to test the ability of infection with the tapeworm Hymenolepis diminuta to ameliorate Freund's complete adjuvant (CFA)-induced monoarthritis in mice. METHODS: Mice received CFA with or without H diminuta, and knee swelling, pain, and measures of inflammation were assessed. RESULTS: Injection of CFA resulted in rapid (within 24 hours) and sustained (lasting 20 days) knee swelling, a decreased pain threshold, increased blood flow to the knee, and increased production of tumor necrosis factor α and interleukin-12p40 (IL-12p40). In mice that were infected with H diminuta 8 days prior to receiving CFA, the severity of arthritis was reduced as assessed by these indices of inflammation and infection 2 days after CFA injection and resulted in more rapid resolution of knee swelling. This antiarthritic effect required a viable infection and was dependent on adaptive immunity, because infection with H diminuta did not protect mice lacking T cells and B cells or the IL-4 receptor α chain from CFA-induced inflammation. Interleukin-10 was of prime importance in the antiarthritic effect, because IL-10-knockout mice were not protected by infection, the antiarthritic effect was ablated by use of neutralizing IL-10 antibodies, and transfer of CD4+ cells from infected wild-type mice but not IL-10-knockout mice significantly reduced CFA-induced knee swelling. CONCLUSION: In mice, the adaptive immune response to infection with H diminuta involves mobilization of IL-10, which has the concomitant advantage of dampening the innate immune responses that drive CFA-induced joint inflammation.

The inhibitory effect against collagen-induced arthritis by Schistosoma japonicum infection is infection stage-dependent.

BACKGROUND: A long-term existing schistosome infection can aid in maintaining immuno-homeostasis, thus providing protection against various types of autoimmune diseases to the infected host. Such benefits have often been associated with acute or egg stage infection and with the egg-induced Th2 response. However, since schistosome infection undergoes different stages, each associated with a specific induction of Th responses, the requirements for the ability of the different stages of schistosome infection to protect against autoimmune disease has not been elucidated. The present study was designed to study whether different stages of schistosome infection offer unique protection in collagen-induced arthritis and its mechanisms. RESULTS: Arthritis susceptible strain DBA/1 male mice were infected with Schistosoma japonicum for either 2 weeks resulting in early stage infection or for 7 weeks resulting in acute or egg stage infection. Following Schistosoma japonicum infection, collagen II was administered to induce collagen-induced arthritis, an animal model for human rheumatoid arthritis. Infection by Schistosoma japonicum significantly reduced the severity and the incidence of experimental autoimmune collagen-induced arthritis. However, this beneficial effect can only be provided by a pre-established acute stage of infection but not by a pre-established early stage of the infection. The protection against collagen-induced arthritis correlated with reduced levels of anti-collagen II IgG, especially the subclass of IgG2a. Moreover, in protected mice increased levels of IL-4 were present at the time of collagen II injection together with sustained higher IL-4 levels during the course of arthritis development. In contrast, in unprotected mice minimal levels of IL-4 were present at the initial stage of collagen II challenge together with lack of IL-4 induction following Schistosoma japonicum infection. CONCLUSION: The protective effect against collagen-induced arthritis provided by Schistosoma japonicum infection is infection stage-dependent. Furthermore, the ability of schistosomiasis to negatively regulate the onset of collagen-induced arthritis is associated with a dominant as well as long-lasting Th2 response at the initiation and development of autoimmune joint and systemic inflammation.

Cyclophosphamide adjuvant arthritis in Trypanosoma cruzi infected rats with inflammatory cytokine effects.

OBJECTIVE: To analyze whether the cyclophosphamide (CYC) induced reestablishment of adjuvant arthritis (AA) in chronically Trypanosoma cruzi infected rats correlates with changes in the secretion of pro- and antiinflammatory cytokines by popliteal lymph node cells. METHODS: Inbred "l" rats infected with T. cruzi 90 days earlier and age matched controls were given CYC (25 mg/kg body weight) or physiologic saline 48 h before arthritis induction. Popliteal lymph node cells were collected at the time of AA induction (48 h after CYC treatment) or during the peak response, to study the concanavalin-A (ConA) or Mycobacterium tuberculosis-driven in vitro proliferation of several cytokines in their culture supernatants. Results. Infected rats given CYC were recovered from the otherwise decreased ConA induced proliferation seen at the time of peak AA. The CYC mediated reestablishment of AA in T. cruzi infected rats coexisted with an increased presence of tumor necrosis factor-a in supernatants from either antigen or ConA stimulated cultures as well as interleukin 12 (IL-12) in the latter case. CYC also lowered to normal the increased IL-10 levels from ConA stimulated cultures that the T. cruzi group displayed at the time of inducing AA. Conclusion. The process by which CYC restores the clinical expression of AA affects the balance between cytokines that influence the regulation of arthritis in favor of the inflammatory component.

Administration of interferon-g to pregnant rats reverses the depressed adjuvant-induced arthritis of their chronically Trypanosoma cruzi-infected offspring.

We demonstrated that administration of interferon gamma (IFN-gamma) to the inbred "I" strain of pregnant rats conferred partial resistance on their offspring to challenge with Trypanosoma cruzi. We now examine if this intervention also modifies the reportedly immunodepressed cellular responses which occur during chronic infection. Offspring were born to mothers undergoing one of the following procedures during gestation: subcutaneous injections of recombinant rat IFN-gamma, 50,000 IU/rat, five times/week for 3 weeks, which was started on the day of mating (IFN-Mo); infection with 10(6) trypomastigotes of T. cruzi at 7, 14, and 21 days after mating plus IFN-gamma treatment as given to the former group (TcIFN-Mo); the same protocol except that physiological saline was injected instead of IFN-gamma (Te-Mo); injection of physiological saline only (control-Mo). All offspring groups (N = 8-10/group) were infected at weaning and were assessed 90 days later for their adjuvant-induced arthritic response or levels of major T cell subsets in spleen and lymph nodes. TcIFN-Mo and IFN-Mo offspring showed a reestablished arthritic response, which remained within the range seen in controls. Immunolabeling studies on parallel groups of 90-day-infected offspring showed that the inverse CD4/CD8 cell ratio that is usually seen in lymphoid organs from these chronically infected rats (median 0.61) appeared to have recovered in the TcIFN-Mo and IFN-Mo groups (median 1.66 and 1.78, respectively) and was not different from uninfected controls (1.96). These studies indicate that early stimulation with IFN-gamma is able to reverse the immunosuppressive state that is usually present during the chronic period of the experimental infection.