Tertiary lymphoid tissues generate effector and memory T cells that lead to allograft rejection.

Tertiary lymphoid tissues are lymph node-like cell aggregates that arise at sites of chronic inflammation. They have been observed in transplanted organs undergoing chronic rejection, but it is not known whether they contribute to the rejection process by supporting local activation of naïve lymphocytes. To answer this question, we established a murine transplantation model in which the donor skin contains tertiary lymphoid tissues due to transgenic expression of lymphotoxin-alpha(RIP-LT alpha), whereas the recipient lacks all secondary lymphoid organs and does not mount primary alloimmune responses. We demonstrate in this model that RIP-LT alpha allografts that harbor tertiary lymphoid tissues are rejected, while wild-type allografts that lack tertiary lymphoid tissues are accepted. Wild-type allografts transplanted at the same time as RIP-LT alpha skin or 60 days later were also rejected, suggesting that tertiary lymphoid tissues, similar to secondary lymphoid organs, generate both effector and memory immune responses. Consistent with this observation, naive T cells transferred to RIP-LT alpha skin allograft but not syngeneic graft recipients proliferated and differentiated into effector and memory T cells. These findings provide direct evidence that tertiary lymphoid structures perpetuate the rejection process by supporting naïve T-cell activation.

Induction of oral tolerance to cellular immune responses in the absence of Peyer's patches.

Systemic hyporesponsiveness occurs following oral administration of antigen (oral tolerance) and involves the uptake and processing of antigen by the gut-associated lymphoid tissue (GALT), which includes Peyer's patches (PP) lamina propria lymphocytes and mesenteric lymph nodes (MLN). Animals with targeted mutations of genes in the tumor necrosis factor (TNF) family have differential defects in the development of peripheral lymphoid organs including PP and MLN, and provide a unique opportunity to investigate the role of GALT structures in the induction of oral tolerance. Oral tolerance could not be induced in TNF/lymphotoxin (LT) alpha-/- mice, which are devoid of both PP and MLN, although these animals could be tolerized by intraperitoneal administration of antigen, demonstrating the requirement for GALT for oral tolerance induction. LTbeta-/- mice and LTalpha/LTbeta+/- animals do not have PP but could be orally tolerized, as measured by IFN-gamma production and delayed-type hypersensitivity responses by administration of both low or high doses of ovalbumin. To further investigate the requirement for PP, we tested the progeny of LTbeta-receptor-IgG-fusion-protein (LTbetaRigG)-treated mice, which do not form PP but have an otherwise intact immune system. Although these animals had decreased fecal IgA production, they could be orally tolerized. Our results demonstrate that PP are not an absolute requirement for the induction of either high- or low-dose oral tolerance, although oral tolerance could not be induced in animals devoid of both PP and MLN.

Resident and infiltrating central nervous system APCs regulate the emergence and resolution of experimental autoimmune encephalomyelitis.

During experimental autoimmune encephalomyelitis (EAE), autoreactive Th1 T cells invade the CNS. Before performing their effector functions in the target organ, T cells must recognize Ag presented by CNS APCs. Here, we investigate the nature and activity of the cells that present Ag within the CNS during myelin oligodendrocyte glycoprotein-induced EAE, with the goal of understanding their role in regulating inflammation. Both infiltrating macrophages (Mac-1(+)CD45(high)) and resident microglia (Mac-1(+)CD45(int)) expressed MHC-II, B7-1, and B7-2. Macrophages and microglia presented exogenous and endogenous CNS Ags to T cell lines and CNS T cells, resulting in IFN-gamma production. In contrast, Mac-1(-) cells were inefficient APCs during EAE. Late in disease, after mice had partially recovered from clinical signs of disease, there was a reduction in Ag-presenting capability that correlated with decreased MHC-II and B7-1 expression. Interestingly, although CNS APCs induced T cell cytokine production, they did not induce proliferation of either T cell lines or CNS T cells. This was attributable to production by CNS cells (mainly by macrophages) of NO. T cell proliferation was restored with an NO inhibitor, or if the APCs were obtained from inducible NO synthase-deficient mice. Thus, CNS APCs, though essential for the initiation of disease, also play a down-regulatory role. The mechanisms by which CNS APCs limit the expansion of autoreactive T cells in the target organ include their production of NO, which inhibits T cell proliferation, and their decline in Ag presentation late in disease.

Lymphotoxin-alpha deficiency completely protects C57BL/6 mice from developing clinical experimental autoimmune myasthenia gravis.

A complete prevention of clinical experimental autoimmune myasthenia gravis (EAMG) was observed in lymphotoxin (LT)-alpha deficient (LT-alpha(-/-)) mice compared to LT-alpha(+/+) mice when immunized with acetylcholine receptor. However, only a partial prevention of clinical EAMG incidence was observed in LT-beta(-/-) mice compared to LT-beta(+/+) mice. LT-alpha(-/-)and LT-beta(-/-) mice had lower mean titers of total IgG, IgG(1), IgG(2a) and IgG(2b) and higher or equal mean titers of IgM anti-AChR antibodies compared to controls. Therefore, LT-alpha(-/-)and LT-beta(-/-) AChR immunized mice are capable of mounting a primary (IgM) humoral immune response to AChR, but are less capable of switching to the pathogenic anti-AChR IgG isotypes. LT could play a significant role in the pathogenesis of myasthenia gravis.

Lymphoid tissue homing chemokines are expressed in chronic inflammation.

Secondary lymphoid tissue chemokine (SLC) and B lymphocyte chemoattractant (BLC) are homing chemokines that have been implicated in the trafficking of lymphocytes and dendritic cells in lymphoid organs. Lymphotoxin-alpha (LTalpha), a cytokine crucial for development of lymphoid organs, is important for expression of SLC and BLC in secondary lymphoid organs during development. Here we report that transgenic expression of LTalpha induces inflammation and ectopic expression of SLC and BLC in the adult animal. LTbeta was not necessary for induction of BLC and SLC in inflamed tissues, whereas, in contrast, tumor necrosis factor receptor-1 was found to be important for the LTalpha-mediated induction of these chemokines. The ectopic expression of LTalpha is associated with a chronic inflammation that closely resembles organized lymphoid tissue and this lymphoid neogenesis can also be seen in several chronic inflammatory diseases, including in the pancreas of the prediabetic nonobese diabetic (NOD) mouse. Expression of SLC was also observed in the pancreas of prediabetic NOD mice. This study implicates BLC and SLC in chronic inflammation and presents further evidence that LTalpha orchestrates lymphoid organogenesis both during development and in inflammatory processes.

Kinetics and cellular origin of cytokines in the central nervous system: insight into mechanisms of myelin oligodendrocyte glycoprotein-induced experimental autoimmune encephalomyelitis.

Experimental autoimmune encephalomyelitis induced by myelin oligodendrocyte glycoprotein (MOG) in C57BL/6 (H-2b) mice is characterized by early (day 12) acute paralysis, followed by a sustained chronic clinical course that gradually stabilizes. Extensive inflammation and demyelination coincide with clinical signs of disease. To identify the mechanisms of these processes, individual proinflammatory and anti-inflammatory cytokines and chemokines were studied. Sensitive single-cell assays were utilized to determine the cellular origin and kinetics of cytokine production in the CNS. Immunization with MOG35-55 peptide resulted in priming of both Th1 (lymphotoxin, IFN-gamma, and TNF-alpha) and Th2 (IL-4) cells in the spleen. However, only Th1 cells were apparent in the CNS. CD4 T cells that produced IFN-gamma or TNF-alpha were present in the CNS by day 7 after immunization with MOG35-55, peaked at day 20, and then waned. TNF-alpha was also produced in the CNS by Mac-1+ cells. On days 7 and 10 after immunization, the TNF-alpha-producing Mac1+ cells were predominantly microglia. By day 14, a switch occurred in that the Mac1+ TNF-alpha-producing cells had the phenotype of infiltrating macrophages. RANTES, IFN-inducible protein 10 (IP-10), and monocyte chemotactic protein 1 chemokine mRNA were detected in the CNS by day 8 after immunization. The early presence of monocyte chemotactic protein 1 (MCP-1) in the CNS provides a mechanism for the recruitment of macrophages. These data implicate TNF-alpha production by a continuum of T cells, microglia, and macrophages at various times during the course of disease. The importance of Th1 cytokines is highlighted, with little evidence for a role of Th2 cytokines.

Lymphoid neo-organogenesis: lymphotoxin's role in inflammation and development.

Lymphoid organ development and inflammation have previously been considered as distinct mechanistically and functionally. In recent years, it has been realized that these phenomena have much in common. This insight has been gained from the recognition that cytokines of the lymphotoxin (LT)/tumor necrosis factor (TNF) family are involved in both processes. The members of the family, LT-alpha, LT-beta, and TNF-alpha, and their multiple receptors participate combinatorially in lymphoid organ development and chronic inflammation. When inflammation that arises in microbial infection or autoimmune disease becomes chronic, it can take on the appearance of organized lymphoid tissue and has been called a tertiary lymphoid organ. Data with transgenic and knockout mice suggest that the process is cytokine-mediated and could be called "lymphoid neo-organogenesis." LT as LT-alpha3 and LT-alpha1beta2 plays a key role in these processes. Data obtained in vitro in an endothelial cell line and in vivo in transgenic and knockout mice indicate that LT influences these events through induction of adhesion molecules such as E-selectin adhesion molecule (ELAM), vascular cell adhesion molecule (VCAM), intercellular adhesion molecule (ICAM), mucosal addressin cellular adhesion molecule (MAdCAM), and peripheral node addressin (PNAd), and chemokines.

Differential induction of adhesion molecule and chemokine expression by LTalpha3 and LTalphabeta in inflammation elucidates potential mechanisms of mesenteric and peripheral lymph node development.

Lymphotoxin (LT) is a member of the proinflammatory TNF family of cytokines that plays a critical role in the development of lymphoid tissue. It has previously been reported that the presence of the LTalpha transgene under the control of the rat insulin promoter results in inflammation at the sites of transgene expression. LTalpha transgene expression results in expression of the adhesion molecules VCAM, ICAM, peripheral node addressin (a marker of peripheral lymph nodes), and mucosal addressin cellular adhesion molecule (a marker of mucosal lymphoid tissue, including mesenteric lymph nodes). In this study to determine the mechanisms by which LT promotes inflammation and lymphoid tissue organization, we analyzed the regulation of expression of adhesion molecules and chemokines in LT transgenic mice. The results demonstrate that LTalpha3 induces expression of the adhesion molecules VCAM, ICAM, and mucosal addressin cellular adhesion molecule as well as the chemokines RANTES, IFN-inducible protein-10, and monocyte chemotactic protein-1, while LTalphabeta is required for the induction of peripheral node addressin that may contribute to the recruitment of L-selectinhigh CD44low naive T cells. These data provide candidate mediators of LT-induced inflammation as well as potential mechanisms by which LTalpha and LTalphabeta may differentially promote the development of mesenteric and peripheral lymph nodes.

Murine neurofibroma reversion by antisense RNA for HTLV-I tax.

Neurofibroma cell lines derived from mice transgenic for HTLV-I LTR tax express high levels of HTLV-I tax mRNA and protein and exhibit a transformed phenotype. A retrovirus vector carrying HTLV-I tax cDNA in reversed transcriptional orientation was stably transfected into the neurofibroma cells. Antisense RNA inhibited expression of the tax gene with a decrease of more than 40% in both tax mRNA and protein. Tax antisense RNA reversed the transformed phenotype as exhibited by dramatic changes in cell morphology and growth characteristics. Expression of several cellular genes which are activated by Tax protein including GM-CSF, IL-6, LT/TNF, c-myc and LIF was down-regulated, while M-CSF and c-src proto-oncogene expressions were up-regulated. Accumulation of beta-actin mRNA was not affected. The changes that occurred in the tax antisense expressing neurofibroma cells could be the consequence of the decreased concentration of Tax protein. These results also indicate that HTLV-I Tax protein is crucial for maintaining the transformed cell morphology, growth and proliferation of murine neurofibroma cells and suggest that deregulation of endogenous cellular genes by Tax protein is the mechanism through which neurofibromas occur in tax mice.

Lymphotoxin alpha3 induces chemokines and adhesion molecules: insight into the role of LT alpha in inflammation and lymphoid organ development.

Lymphotoxin (LT) plays an important role in inflammation and lymphoid organ development, though the mechanisms by which it promotes these processes are poorly understood. Toward this end, the biologic activities of a recently generated recombinant murine (m) LT alpha preparation were evaluated. This cytokine preparation was effective at inducing cytotoxicity of WEHI target cells with 50% maximal killing observed with 1.2 ng/ml. mLT alpha also induced the expression of inflammatory mediators in the murine endothelial cell line bEnd.3. rmLT alpha induced expression of the adhesion molecules VCAM, ICAM, E-selectin, and the mucosal addressin cellular adhesion molecule, MAdCAM-1. When mLT alpha, human (h) LT alpha, and mTNF-alpha were compared, mLT alpha was the most potent inducer of MAdCAM-1. None of these cytokines induced the peripheral node addressin, PNAd. mLT alpha also induced expression of the chemokines RANTES, IFN-inducible protein 10 (IP-10), and monocyte chemotactic protein 1 (MCP-1). mRNA levels peaked 4 h following treatment with mLT alpha and declined through the 24-h treatment period. LT alpha also induced chemokine protein within 8 h of treatment, which increased through the 24-h treatment period. These data demonstrate that the proinflammatory effects of LT alpha3 may be mediated in part through the induction of adhesion molecule and chemokine expression. Further, LT alpha3 may promote development of lymphoid tissue through induction of chemokines and the mucosal addressin MAdCAM-1. These data confirm previous observations in transgenic and knockout mice that LT alpha3 in the absence of LT beta carries out unique biologic activities.

Differential activities of secreted lymphotoxin-alpha3 and membrane lymphotoxin-alpha1beta2 in lymphotoxin-induced inflammation: critical role of TNF receptor 1 signaling.

Lymphotoxin (LT, LT alpha, TNF beta) is a member of the immediate TNF family that also includes TNF-alpha and lymphotoxin-beta (LT beta). LT is produced by activated lymphocytes and functions as either a secreted homotrimer or a membrane-associated heterotrimer that includes the transmembrane protein LT beta. Secreted LT alpha3 can bind to two cell surface receptors, TNFR1 and TNFR2, while the membrane-bound heterotrimer LT alpha1beta2 has been shown to interact with a distinct receptor, LT betaR. LT alpha induces inflammation at the sites of expression of a rat insulin promoter-driven lymphotoxin (RIPLT) transgene in the pancreas and kidney. To determine the role of the various ligands and their receptors in LT-induced inflammation, mice deficient in either TNFR1, TNFR2, or LT beta were crossed to RIPLT-transgenic mice. Our results indicate that LT alpha-induced inflammation is dependent on the interaction of LT alpha3 with TNFR1, and there is no obvious role for TNFR2, since in its absence, LT alpha-induced inflammation is quantitatively and qualitatively similar to that seen in the wild type. However, the absence of LT beta results in accentuated infiltration of the kidney with an increase in the proportion of memory cells in the infiltrate. These data show a crucial role for the secreted LT alpha3 signaling via TNFR1 in LT alpha-induced inflammation, and a separate and distinct role for the membrane LT alpha1beta2 form in this inflammatory process.

Transgenic expression of lymphotoxin restores lymph nodes to lymphotoxin-alpha-deficient mice.

Lymphotoxin-alpha (LT alpha) has recently been demonstrated to be important in the development of lymph nodes (LN), Peyer's patches, and splenic organization, including the development of germinal centers. To elucidate the role of LT alpha in lymphoid organogenesis and the plasticity of the process, we examined LT alpha-/- mice in which an LT alpha transgene under the control of the rat insulin promoter (RIPLT) is expressed in the pancreas, kidney, and skin. The LT alpha transgene restored LN in LT alpha-/- mice. The reconstituted LN of RIPLT.LT alpha-/- mice had germinal center-like peanut agglutinin-positive regions, but lacked follicular dendritic cells. Although the LT alpha transgene did not restore Peyer's patches or splenic architecture, it restored the ability of the spleen to form germinal centers and follicular dendritic cell networks. Lymphocytes isolated from the reconstituted LN showed normal proliferative responses to T and B cell mitogens and were defective in their proliferative response to T-dependent Ag, and a decreased number of interdigitating dendritic cells was apparent in the RIPLT.LT alpha-/- mice LN. Expression of the RIPLT transgene in mice deficient in LT beta did not reconstitute LN, suggesting an important role for LT beta in the mechanisms that reconstitute LN in RIPLT.LT alpha-/- mice. These data are the first to demonstrate reconstitution of LN in LT alpha-/- mice and show that the process of LN restoration is amenable to manipulation with ectopic lymphotoxin.

A critical role for lymphotoxin in experimental allergic encephalomyelitis.

The lymphotoxin (LT)/tumor necrosis factor (TNF) family has been implicated in the neurologic inflammatory diseases multiple sclerosis (MS) and experimental allergic encephalomyelitis (EAE). To determine the role of individual family members in EAE, C57BL/6 mice, LT-alpha-deficient (LT-alpha-/- mice), or LT-beta-deficient (LT-beta-/- mice), and their wild-type (WT) littermates were immunized with rat myelin oligodendrocyte glycoprotein (MOG) peptide 35-55. C57BL/6 and WT mice developed chronic, sustained paralytic disease with average maximum clinical scores of 3.5 and disease indices (a measure of day of onset and sustained disease scores) ranging from 367 to 663 with central nervous system (CNS) inflammation and demyelination. LT-alpha-/- mice were primed so that their splenic lymphocytes proliferated in response to MOG 35-55 and the mice produced anti-MOG antibody. However, LT-alpha-/- mice were quite resistant to EAE with low average clinical scores (<1), an average disease index of 61, and the negligible CNS inflammation and demyelination. WT T cells transferred EAE to LT-alpha-/- recipients. LT-beta-/- mice were susceptible to EAE, though less than WT, with an average maximum clinical score of 1.9 and disease index of 312. These data implicate T cell production of LT-alpha in MOG EAE and support a major role for LT-alpha3, a minor role for the LT-alpha/beta complex, and by inference, no role for TNF-alpha.

Presentation via the class I pathway by Leishmania amazonensis-infected macrophages of an endogenous leishmanial antigen to CD8+ T cells.

CD8+ T cells play a protective role in immunity to cutaneous leishmaniasis. However, it has been unclear how these cells execute this function, since results from several investigations attempting to demonstrate recognition of Leishmania-infected macrophages by CD8+ T cells have been contradictory. In this study, we report the generation of CD8+ T cell lines specific for GP46/M-2, a leishmanial Ag, previously shown to protectively immunize mice against a Leishmania amazonensis challenge. Using T cell cytolysis and IFN-gamma production to assess CD8+ T cell activation, we show that in addition to recognizing mammalian cells transfected with GP46/M-2, these CD8+ T cell lines also recognize macrophages infected with Leishmania amazonensis. MHC class I presentation of GP46/M-2 by infected macrophages can be blocked by treatment with brefeldin A and also by inhibitors of the cytosolic multicatalytic proteasome, N-acetyl-L-leucinyl-L-leucinal-L-norleucinal and N-acetyl-L-leucinyl-L-leucinylmethional. These results suggest that this leishmanial Ag is processed in the macrophage cytoplasm and is presented to CD8+ T cells via the classical pathway of MHC class I presentation. The relevance of these findings as they impact on our understanding of the biology of the parasite within the macrophage is discussed.

Distinct roles in lymphoid organogenesis for lymphotoxins alpha and beta revealed in lymphotoxin beta-deficient mice.

Lymphotoxin alpha (LT alpha)-deficient mice revealed critical roles for LT alpha in lymphoid organogenesis, but it is not clear whether LT alpha functions through an LT alpha homotrimer (LT alpha3) or LT alpha/beta heterotrimers. We generated LTbeta-deficient mice and found them to lack Peyer's patches, peripheral lymph nodes, splenic germinal centers, and follicular dendritic cells. Unlike LT alpha-deficient mice, LT beta-deficient mice had cervical and mesenteric lymph nodes. Furthermore, the mesenteric lymph nodes had germinal center-like regions, although these structures appeared to lack follicular dendritic cells. The absence of cervical and mesenteric lymph nodes in LT alpha-deficient mice, and yet their presence in LT beta-deficient mice and in mice deficient in tumor necrosis factor receptor types I and II, suggest that LT alpha3 may signal via an as yet unidentified receptor.

Lymphotoxin-beta and TNF regulation in T cell subsets: differential effects of PGE2.

The effects of prostaglandin E2 (PGE2) on lymphotoxin beta (LT-beta) and tumour necrosis factor alpha (TNF) were assessed in murine CD4+ Th1 and Th2 T cell clones. LT-beta mRNA was constitutively expressed by both T cell subsets. However, PGE2 inhibited its accumulation only in Th1, but not Th2 clones. PGE2 inhibited TNF mRNA accumulation and production and release of bioactive material by both Th1 and Th2 T cells. The effects of PGE2 were also evaluated on production of IL-3, another cytokine produced by both T cell subsets, and interleukin 4 (IL-4), which is produced only by Th2 cells. Though IL-3 was produced by both T cell subsets it was only inhibited in Th1 cells, a pattern similar to that observed for LT-beta. Accumulation of IL-4 mRNA in Th2 cells was not inhibited by PGE2. These results demonstrate that PGE2 does not affect LT-beta, IL-4, or IL-3 in Th2 cells, but inhibits TNF mRNA accumulation and production in this T cell subset. Thus, TNF appears to be the only cytokine susceptible to inhibition by PGE2 in Th2 cells. The fact that PGE2 inhibits LT-beta and IL-3 in Th1 but not Th2 cells points to a different mechanism of regulation of the same cytokine in different subsets. The mechanisms that contribute to TNF mRNA accumulation also may differ in the two CD4+ T cell subsets, because cycloheximide superinduced TNF mRNA in Th2 cells, but not in Th1 cells. The inhibitory effects of PGE2 on TNF mRNA accumulation by either T cell subset did not require de novo protein synthesis since preincubation with the protein synthesis inhibitor, cycloheximide, did not alter the PGE2-mediated effects. Cross-regulation of cytokine production and function has been demonstrated for both T cell subsets, and PGE2 may modulate the outcome of an immune response via differential regulation of cytokine production.

Leishmania-infected macrophages sequester endogenously synthesized parasite antigens from presentation to CD4+ T cells.

CD4+ T cell lines raised against the protective leishmanial antigens GP46 and P8 were used to study the presentation of endogenously synthesized Leishmania antigens by infected cells. Using two different sources of macrophages, the I4.07 macrophage cell line (H-2k) which constitutively expresses major histocompatibility complex (MHC) class II molecules, and elicited peritoneal exudate cells, we found that cells infected with Leishmania amastigotes presented little, if any endogenously synthesized parasite antigens to CD4+ T cells. In contrast, promastigote-infected macrophages did present endogenous parasite molecules to CD4+ T cells, although only for a limited time, with maximal presentation occurring within 24 h of infection and decreasing to minimal antigen presentation at 72 h post-infection. These observations suggest that once within the macrophage, Leishmania amastigote antigens are sequestered from the MHC class II pathway of antigen presentation. This allows live parasites to persist in infected hosts by evading the activation of CD4+ T cells, a major and critical anti-leishmanial component of the host immune system. Studies with drugs that modify fusion patterns of phagosomes suggest that the mechanism of this antigen sequestration includes targeted fusion of the parasitophorous vacuole with certain endocytic compartments.

Chronic inflammation caused by lymphotoxin is lymphoid neogenesis.

In presenting a unifying concept for chronic inflammation and lymphoid organogenesis, we suggest that lymphotoxin's (LT, LT-alpha, TNF-beta) crucial role in these processes is pivotal and similar. Chronic inflammatory lesions that developed in the kidney and pancreas at the sites of transgene expression in rat insulin promoter-LT (RIP-LT) mice resembled lymph nodes with regard to cellular composition (T cells, B cells, plasma cells, and antigen-presenting cells), delineated T and B cell areas, primary and secondary follicles, characteristic morphologic and antigenic (ICAM-1, VCAM-1, MAdCAM-1, and PNAd) features of high endothelial venules, and ability to respond to antigen and undergo Ig class switching when obtained from mice immunized with SRBC. The vascular changes, with the exception of PNAd, appear to be the direct consequence of transgene derived LT expression, as they were also observed in RIP-LT mice lacking mature T and B cells. These data show that LT-induced chronic inflammation has the characteristics of organized lymphoid tissue.

Disruption of CD40-CD40 ligand interactions results in an enhanced susceptibility to Leishmania amazonensis infection.

To study the role of CD40 ligand (CD40L) in the host immune responses against intracellular pathogens, we infected CD40L knockout (CD40L-/-) mice with Leishmania amazonensis. Although wild-type mice were susceptible to infection and developed progressive ulcerative lesions, tissue parasite burdens in CD40L-/- mice were significantly higher. This heightened susceptibility to infection was associated with an impaired T cell and macrophage activation and altered inflammatory response, as reflected by low levels of IFN gamma, lymphotoxin-tumor necrosis factor (LT-TNF), and nitric oxide (NO) production. Furthermore, CD40L-/- mice failed to generate a protective immune response after immunization. These results indicate an essential role of cognate CD40-CD40L interactions in the generation of cellular immune responses against an intracellular parasite.

The contribution of insulitis to diabetes development in tumor necrosis factor transgenic mice.

The inflammatory response mediated by cytokines such as TNF can promote recruitment of lymphocytes to a tissue. Moreover, if other conditions are met, this can provide a predisposing role to autoimmune disease. TNFs induce the appearance of adhesion molecules (and presumably, therefore, extravasation of lymphocytes into tissue from the vasculature) and increase the levels of MHC class I on tissue. However, it is not clear which of these effects plays the key role in induction of disease. This should be the subject of further study. The data substantiate the hypothesis that chronic inflammation might play a precipitating role in autoimmunity and could be one of the environmental factors of importance in the development of so many autoimmune diseases.