Prevention of Th2-mediated murine allergic airways disease by soluble antigen administration in the neonate

It has been demonstrated recently that neonatal antigen administration in the mouse can lead to priming for Th2-mediated immune responses. This observation has important implications for the development of vaccination strategies in humans, particularly for individuals who may be predisposed to atopy or asthma. In this paper it is shown that although i.p. administration of antigen (100 μg) in adjuvant to the neonate does indeed prime for Th2-mediated disease in mice [allergic airways disease (AAD)], when the same relatively low dose of antigen is given in soluble form no priming occurs. Further, administration of a larger dose of soluble antigen (1 mg) actually prevents the ability to prime for a Th2 response subsequently and so prevents the induction of AAD. Protection from disease was associated with evidence of functional inactivation of both Th1 and Th2 ovalbumin-specific T cells. In contrast, administration of a very low dose of antigen (10 μg) primed for a Th2 response in a similar fashion to antigen in adjuvant. We suggest that the adjuvant lowers the “effective” dose of antigen administered in the neonate and thereby primes for Th2-type immune responses. These findings demonstrate that neonatal antigen administration can inhibit Th2-mediated diseases, such as AAD, but the dose of antigen may be critical to avoid predisposition to disease.     

Activated rat hepatic stellate cells influence Th1/Th2 profile in vitro

AIM: To investigate the effects of activated rat hepatic stellate cells(HSCs) on rat Th1/Th2 profile in vitro.METHODS: Growth and survival of activated HSCs and CD4+ T lymphocytes cultured alone or together was assessed after 24 or 48 h. CD4+ T lymphocytes were then cultured with or without activated HSCs for 24 or 48 h and the proportion of Th1 [interferon(IFN)-γ+] and Th2 [interleukin(IL)-4+] cells was assessed by flow cytometry. Th1 and Th2 cell apoptosis was assessed after 24 h of co-culture using a caspase-3 staining procedure. Differentiation rates of Th1 and Th2 cells from CD4+ T lymphocytes that were positive for CD25 but did not express IFN-γ or IL-4 were also assessed after 48 h of co-culture with activated HSCs. Galectin-9 expression in HSCs was determined by immunofluorescence and Western blotting. ELISA was performed to assess galectin-9 secretion from activated HSCs.RESULTS: Co-culture of CD4+ T lymphocytes with activated rat HSCs for 48 h significantly reduced the proportion of Th1 cells compared to culture-alone conditions(-1.73% ± 0.71%; P 0.05), whereas the proportion of Th2 cells was not altered; the Th1/Th2 ratio was significantly decreased(-0.44 ± 0.13; P 0.05). In addition, the level of IFN-γ in Th1 cells wasdecreased(-65.71 ± 9.67; P 0.01), whereas the level of IL-4 in Th2 cells was increased(82.79 ± 25.12; P 0.05) by co-culturing, as measured by mean fluorescence intensity by flow cytometry. Apoptosis rates in Th1(12.27% ± 0.99%; P 0.01) and Th2(1.71% ± 0.185%; P 0.01) cells were increased 24 h after co-culturing with activated HSCs; the Th1 cell apoptosis rate was significantly higher than in Th2 cells(P 0.01). Galectin-9 protein expression was significantly decreased in HSCs only 24 h after coculturing(P 0.05) but not after 48 h. Co-culture for 48 h significantly increased the differentiation of Th1 and Th2 cells; however, the increase in the proportion of Th2 cells was significantly higher than that of Th1 cells(1.85% ± 0.48%; P 0.05).CONCLUSION: Activated rat HSCs lower the Th1/Th2 profile, inhibiting the Th1 response and enhancing the Th2 response, and this may be a novel pathway for liver fibrogenesis.     

Conversion of Th2 memory cells into Foxp3+ regulatory T cells suppressing Th2-mediated allergic asthma

Genetic and epigenetic programming of T helper (Th) cell subsets during their polarization from naive Th cells establishes long-lived memory Th cells that stably maintain their lineage signatures. However, whether memory Th cells can be redifferentiated into another Th lineage is unclear. In this study, we show that Ag-specific memory Th cells were redifferentiated into Foxp3⁺ T cells by TGF-β when stimulated in the presence of all-trans retinoic acid and rapamycin. The “converted” Foxp3⁺ T cells that were derived from Th2 memory cells down-regulated GATA-3 and IRF4 and produced little IL-4, IL-5, and IL-13. Instead, the converted Foxp3⁺ T cells suppressed the proliferation and cytokine production of Th2 memory cells. More importantly, the converted Foxp3⁺ T cells efficiently accumulated in the airways and significantly suppressed Th2 memory cell-mediated airway hyperreactivity, eosinophilia, and allergen-specific IgE production. Our findings reveal the plasticity of Th2 memory cells and provide a strategy for adoptive immunotherapy for the treatment of allergic diseases.     

T cell antigen receptor-mediated activation of the Ras/mitogen-activated protein kinase pathway controls interleukin 4 receptor function and type-2 helper T cell differentiation

The central role of type-2 helper T (Th2) cells in the development of allergic responses and immune responses against helminthic parasites is well documented. The differentiation of Th2 cells from naive T cells requires both the recognition of antigen by T cell antigen receptors (TCR) and the activation of downstream signal-transduction molecules of the interleukin 4 receptor (IL-4R) pathway, including Jak1, Jak3, and STAT6. Little is known, however, about how these two distinct pathways cooperate with each other to induce Th2 cells. Here, we use a T cell-specific H-Ras-dominant-negative transgenic mouse to show that TCR-mediated activation of the Ras/mitogen-activated protein kinase pathway alters IL-4R function and is required for Th2 cell differentiation. The enhancement of IL-4R signaling seems to be a consequence of both direct “crosstalk” with the TCR signaling pathway and increased protein expression of downstream signaling molecules of the IL-4R pathway. Therefore, successful Th2 differentiation depends on the effectiveness of the TCR-mediated activation of the Ras/mitogen-activated protein kinase pathway in modifying the IL-4R-mediated signaling pathway.     

Dysregulation of innate immunity in ulcerative colitis patients who fail anti-tumor necrosis factor therapy

AIM To study the innate immune function in ulcerative colitis(UC) patients who fail to respond to anti-tumor necrosis factor(TNF) therapy.METHODS Effects of anti-TNF therapy, inflammation and medications on innate immune function were assessed by measuring peripheral blood mononuclear cell(PBMC) cytokine expression from 18 inflammatory bowel disease patients pre- and 3 mo post-anti-TNF therapy. Toll-like receptor(TLR) expression and cytokine production post TLR stimulation was assessed in UC "responders"(n = 12) and "non-responders"(n = 12) and compared to healthy controls(n = 12). Erythrocyte sedimentation rate(ESR) and C-reactive protein(CRP) levels were measured in blood to assess disease severity/activity and inflammation. Pro-inflammatory(TNF, IL-1β, IL-6), immuno-regulatory(IL-10), Th1(IL-12, IFNγ) and Th2(IL-9, IL-13, IL-17A) cytokine expression was measured with enzyme-linked immunosorbent assay while TLR cellular composition and intracellular signalling was assessed with FACS.RESULTS Prior to anti-TNF therapy, responders and nonresponders had similar level of disease severity and activity. PBMC's ability to respond to TLR stimulation was not affected by TNF therapy, patient's severity of the disease and inflammation or their medication use. At baseline, non-responders had elevated innate but not adaptive immune responses compared to responders(P 0.05). Following TLR stimulation, nonresponders had consistently reduced innate cytokine responses to all TLRs compared to healthy controls(P 0.01) and diminished TNF(P 0.001) and IL-1β(P 0.01) production compared to responders. This innate immune dysfunction was associated with reduced number of circulating plasmacytoid dendritic cells(p DCs)(P 0.01) but increased number of CD4+ regulatory T cells(Tregs)(P = 0.03) as well as intracellular accumulation of IRAK4 in non-responders following TLR-2,-4 and-7 activation(P 0.001). CONCLUSION Reduced innate immunity in non-responders may explain reduced efficacy to anti-TNF therapy. These serological markers may prove useful in predicting the outcome of costly anti-TNF therapy.     

Immunization of Mice by BCG Formulated HCV Core Protein Elicited Higher Th1-Oriented Responses Compared to Pluronic-F127 Copolymer

Background

A supreme vaccine for Hepatitis C virus (HCV) infection should elicit strong Th1-oriented cellular responses. In the absence of a Th1-specific adjuvant, immunizations by protein antigens generally induce Th2-type and weak cellular responses.

Objectives

To evaluate the adjuvant effect of BCG in comparison with nonionic copolymer-Pluronic F127 (F127) as a classic adjuvant in the formulation of HCV core protein (HCVcp) as a candidate vaccine for induction of Th1 immune responses.

Materials and Methods

Expression of N-terminally His-Tagged HCVcp (1-122) by pIVEX2.4a-core vector harboring the corresponding gene under the control of arabinose-inducible (araBAD) promoter was achieved in BL21-AI strain of E.coli and purified through application of nitrilotriacetic acid (Ni-NTA) chromatography. Mice were immunized subcutaneously (s.c.) in base of the tail with 100 μl of immunogen (F127+HCVcp or BCG+HCVcp; 5 μgHCVcp/mouse/dose) or control formulations (PBS, BCG, F127) at weeks 0, 3, 6. Total and subtypes of IgG, as well as cellular immune responses (Proliferation, In vivo CTL and IFN-γ/IL-4 ELISpot assays against a strong and dominant H2-d restricted, CD8+-epitopic peptide, core 39-48; RRGPRLGVRA of HCVcp) were compared in each group of immunized animals.

Results

Expression and purification of core protein around the expected size (21 kDa) was confirmed by Western blotting. The HCVcp + BCG vaccinated mice showed significantly higher lymphocyte proliferation and IFN-γ production but lower levels of cell lysis (45% versus 62% in CTL assay) than the HCVcp+F127 immunized animals. “Besides, total anti-core IgG and IgG1 levels were significantly higher in HCVcp + F127 immunized mice as compared to HCVcp + BCG vaccinated animals, indicating relatively higher efficacy of F127 for the stimulation of humoral and Th2-oriented immune responses”.

Conclusions

Results showed that HCVcp + BCG induced a moderate CTL and mixed Th1/Th2 immune responses with higher levels of cell proliferation and IFN-γ secretion, indicating that BCG may have a better outcome when formulated in HCVcp-based subunit vaccines.     

T-Cell Responses after Rotavirus Infection or Vaccination in Children: A Systematic Review

Cellular immunity against rotavirus in children is incompletely understood. This review describes the current understanding of T-cell immunity to rotavirus in children. A systematic literature search was conducted in Embase, MEDLINE, Web of Science, and Global Health databases using a combination of “t-cell”, “rotavirus” and “child” keywords to extract data from relevant articles published from January 1973 to March 2020. Only seventeen articles were identified. Rotavirus-specific T-cell immunity in children develops and broadens reactivity with increasing age. Whilst occurring in close association with antibody responses, T-cell responses are more transient but can occur in absence of detectable antibody responses. Rotavirus-induced T-cell immunity is largely of the gut homing phenotype and predominantly involves Th1 and cytotoxic subsets that may be influenced by IL-10 Tregs. However, rotavirus-specific T-cell responses in children are generally of low frequencies in peripheral blood and are limited in comparison to other infecting pathogens and in adults. The available research reviewed here characterizes the T-cell immune response in children. There is a need for further research investigating the protective associations of rotavirus-specific T-cell responses against infection or vaccination and the standardization of rotavirus-specific T-cells assays in children.     

DNA vaccination in rhesus macaques induces potent immune responses and decreases acute and chronic viremia after SIVmac251 challenge

Optimized plasmid DNAs encoding the majority of SIVmac239 proteins and delivered by electroporation (EP) elicited strong immune responses in rhesus macaques. Vaccination decreased viremia in both the acute and chronic phases of infection after challenge with pathogenic SIVmac251. Two groups of macaques were vaccinated with DNA plasmids producing different antigen forms, “native” and “modified,” inducing distinct immune responses. Both groups showed significantly lower viremia during the acute phase of infection, whereas the group immunized with the native antigens showed better protection during the chronic phase (1.7 log decrease in virus load, P = 0.009). Both groups developed strong cellular and humoral responses against the DNA vaccine antigens, which included Gag, Pol, Env, Nef, and Tat. Vaccination induced both central memory and effector memory T cells that were maintained at the day of challenge, suggesting the potential for rapid mobilization upon virus challenge. The group receiving the native antigens developed higher and more durable anti-Env antibodies, including neutralizing antibodies at the day of challenge. These results demonstrate that DNA vaccination in the absence of any heterologous boost can provide protection from high viremia comparable to any other vaccine modalities tested in this macaque model.     

Improvement in Th1/Th2 immune homeostasis,antioxidative status and resistance to pathogenic E. coli on consumption of probiotic Lactobacillus rhamnosus fermented milk in aging mice

Imbalance in Th1/Th2 immune pathways and cellular antioxidant systems with progressive aging are among the leading causes of increased risk of morbidity and mortality in elderly. Although probiotics have been considered to boost immune system, there is a lack of comprehensive analysis of probiotic effects on aging physiology. The present study aimed at determining anti-immunosenescence potential of milk fermented with probiotic Lactobacillus rhamnosus (LR) in 16 months old mice by concurrent analysis of immunosenescence markers associated with Th1/Th2 profile of splenocytes, inflamm-aging in plasma, neutrophil functions and antibody response in intestine along with analysis of antioxidant enzymes in liver and red blood cells (RBCs) after feeding trials of 1 and 2 months, respectively. An enteropathogenic Escherichia coli (ATCC 14948)-based infection model in aging mice was also designed to validate protective attributes of LR. Splenocytes registered increased IFN-γ and decreased IL-4 and IL-10 production in LR-fed animals. Neutrophil respiratory burst enzymes and phagocytosis increased significantly while no aggravation in plasma levels of MCP-1 and TNF-α was observed. Further, owing to increased Th1 response, antibodies registered a decrease in IgG1/IgG2a ratio and IgE levels in LR groups. No significant variations were observed in secretory IgA and IgA + cells in the intestine. Antioxidant enzymes (superoxide dismutase, catalase, glutathione peroxidase) in LR-fed groups recorded increased activities which were more pronounced in the liver than in RBCs. LR supplementation significantly reduced E. coli translocation to organs (intestine, liver, spleen, peritoneal fluid) by enhancing E. coli-specific antibodies (IgA and IgG1) and inflammatory proteins. In conclusion, LR supplementation alleviated immunosenescence-associated Th1/Th2 imbalance, improved antioxidant capacity, and enhanced resistance of aged mice to E. coli infection thereby signifying its potential in augmenting healthy aging.     

Feasibility of Spotlight Consultations Tool in Routine Care: Real-World Evidence

Background:Burnout in people with diabetes and healthcare professionals (HCPs) is at an all-time high. Spotlight AQ, a novel “smart” adaptive patient questionnaire, is designed to improve consultations by rapidly identifying patient priorities and presenting these in the context of best-practice care pathways to aid consultations. We aimed to determine Spotlight AQ’s feasibility in routine care.Materials and Methods:The Spotlight prototype tool was trialed at three centers: two UK primary care centers and one US specialist center (June-September 2020). Participants with type 1 (T1D) or type 2 diabetes (T2D) completed the questionnaire prior to their routine consultations. Results were immediately available and formed the basis of the clinical discussion and decision-making within the clinic visit.Results:A convenience sample of 49 adults took part, n=31 T1D, (n=18 female); and n=18 T2D (n=10 male, n=4 female, n=4 gender unreported). Each identified two priority concerns. “Psychological burden of diabetes” was the most common priority concern (T1D n = 27, 87.1%) followed by “gaining more skills about particular aspects of diabetes” (T1D n=19, 61.3%), “improving support around me” (n=8, 25.8%) and “diabetes-related treatment issues” (n=8, 25.8%). Burden of diabetes was widespread as was lack of confidence around self-management. Similarly, psychological burden of diabetes was the primary concern for participants with T2D (n=18,100%) followed by “gaining more skills about aspects of diabetes” (n=7, 38.9%), “improving support around me” (n=7, 38.9%) and “diabetes-related treatment issues” (n=4; 22.2%).Conclusions:Spotlight AQ is acceptable and feasible for use in routine care. Gaining more skills and addressing the psychological burden of diabetes are high-priority areas that must be addressed to reduce high levels of distress.     

The nature of the lymphopenic environment dictates protective function of homeostatic-memory CD8+ T cells

A functional memory T cell pool is critical for resistance to pathogen reinfection. Lymphopenia produces memory-like CD8⁺ T cells through homeostatic proliferation, and such “HP-memory” cells can control lethal bacterial infections similarly to conventional, antigen-experienced, memory T cells. These 2 pathways for memory T cell generation are quite distinct. We show here, however, that similar factors are required for production of protective memory CD8 T cells via both homeostatic and conventional pathways. Induction of protective HP-memory CD8 T cells requires CD4⁺ T cell “help,” which we show is antigen nonspecific yet requires CD40L–CD40 interactions with host cells. The functional competence of HP-memory CD8 T cells also requires release of endogenous bacterial components (which follows irradiation-induced lymphopenia), potentially mimicking the role of adjuvants in conventional immune responses. Lymphopenic environments lacking these key factors support similar CD8 T cell homeostatic proliferation and the acquisition of memory phenotype, yet the HP-memory cells generated are defective in pathogen elimination. These findings suggest unexpected parallels in the requirements for generating protective memory CD8 T cells by distinct pathways, and they suggest ways to bolster immune competence during recovery from lymphopenia.     

IL-1 family members and STAT activators induce cytokine production by Th2, Th17, and Th1 cells

Expression of T1ST2, the IL-33R, by Th2 cells requires GATA3. Resting Th2 cells express little GATA3, which is increased by IL-33 and a STAT5 activator, in turn increasing T1ST2 from its low-level expression on resting Th2 cells. Th2 cells that have upregulated T1ST2 produce IL-13, but not IL-4, in response to IL-33 plus a STAT5 activator in an antigen-independent, NF-κB-dependent, cyclosporin A (CsA)-resistant manner. Similarly, Th17 cells produce IL-17A in response to IL-1β and a STAT3 activator and Th1 cells produce IFNγ in response to IL-18 and a STAT4 inducer. Thus, each effector Th cell produces cytokines without antigenic stimulation in response to an IL-1 family member and a specific STAT activator, implying an innate mechanism through which memory CD4 T cells are recruited by an induced cytokine environment.     

Virtual memory CD8 T cells display unique functional properties

Previous studies revealed the existence of foreign antigen-specific memory phenotype CD8 T cells in unimmunized mice. Considerable evidence suggests this population, termed “virtual memory” (VM) CD8 T cells, arise via physiological homeostatic mechanisms. However, the antigen-specific function of VM cells is poorly characterized, and hence their potential contribution to immune responses against pathogens is unclear. Here we show that naturally occurring, polyclonal VM cells have unique functional properties, distinct from either naïve or antigen-primed memory CD8 T cells. In striking contrast to conventional memory cells, VM cells showed poor T cell receptor-induced IFN-γ synthesis and preferentially differentiated into central memory phenotype cells after priming. Importantly, VM cells showed efficient control of Listeria monocytogenes infection, indicating memory-like capacity to eliminate certain pathogens. These data suggest naturally arising VM cells display unique functional traits, allowing them to form a bridge between the innate and adaptive phase of a response to pathogens.     

Helminth products bypass the need for TSLP in Th2 immune responses by directly modulating dendritic cell function

Thymic stromal lymphopoietin (TSLP) is an interleukin (IL)-7-like cytokine, mainly expressed by epithelial cells, and key to the development of allergic responses. The well-documented involvement of TSLP in allergy has led to the conviction that TSLP promotes the development of inflammatory Th2 cell responses. However, we now report that the interaction of TSLP with its receptor (TSLPR) has no functional impact on the development of protective Th2 immune responses after infection with 2 helminth pathogens, Heligmosomoides polygyrus and Nippostrongylus brasiliensis. Mice deficient in the TSLP binding chain of the TSLPR (TSLPR^−/−) exhibited normal Th2 cell differentiation, protective immunity and memory responses against these two distinct rodent helminths. In contrast TSLP was found to be necessary for the development of protective Th2 responses upon infection with the helminth Trichuris muris (T. muris). TSLP inhibited IL-12p40 production in response to T. muris infection, and treatment of TSLPR^−/− animals with neutralizing anti-IL-12p40 monoclonal antibody (mAb) was able to reverse susceptibility and attenuate IFN-γ production. We additionally demonstrated that excretory-secretory (ES) products from H. polygyrus and N. brasiliensis, but not T. muris, were capable of directly suppressing dendritic cell (DC) production of IL-12p40, thus bypassing the need for TSLP. Taken together, our data show that the primary function of TSLP is to directly suppress IL-12 secretion, thus supporting Th2 immune responses.CD4⁺ T cells can differentiate into Th1, Th2, Th17, and Treg subsets, whose different immunological functions are associated with the production of particular cytokines (1). Of these subsets, Th2 cells play a pivotal role in immunity against helminth infection and are responsible for the pathology associated with allergic disorders (2, 3). Th2 cells typically produce IL-4, IL-5, IL-13, and IL-9 resulting in antibody-isotype switching to IgE, eosinophilia, basophilia, mucin production, and smooth muscle cell hyperreactivity (1).Extensive work has highlighted the key polarizing factors underlying the development of Th1, Th2, Th17, and Treg cells. IL-4 acts as both an effector cytokine and a Th2-polarizing factor (4, 5), although the early signals influencing T cell IL-4 production remain unclear. TSLP activates human DC to up-regulate costimulatory molecules, produce Th2 cell-attracting chemokines, and to promote the production of IL-4, IL-5, IL-13, and TNF-α, but not IL-10, by naïve CD4⁺ T cells (6, 7). TSLP simultaneously fails to activate DC IL-12 secretion (6, 7) and can even inhibit LPS-induced IL-12 production by murine DC in vitro (8, 9). More recently, TSLP has been reported to act directly on naïve mouse CD4⁺ T cells to promote IL-4 production in vitro (10), and to promote Th2 cytokine production by skin-infiltrating effector T cells in vivo (11). Consistent with its role in Th2 differentiation and effector function, TSLPR^−/− mice exhibit strongly attenuated allergic airway (12, 13) and skin inflammation (11), whereas over-expression of TSLP in lung epithelial cells or keratinocytes causes spontaneous allergic inflammation within the respective tissues (13, 14).In the current study, we investigated the impact of TSLP-TSLPR signaling on protective Th2 immune responses against the helminths H. polygyrus and N. brasiliensis, of the Trichostrongyloidea superfamily and T. muris, of the Trichineloidea superfamily. Protective immunity against all 3 helminths requires Th2 immune responses and is abrogated in the absence of Stat6-mediated IL-4/IL-13 signals (15–18). H. polygyrus and N. brasiliensis elicit strong Th2 immune responses in most mouse strains investigated (19). In contrast, the response elicited against T. muris is highly dependent on the genetic background of the host, with resistance or susceptibility tightly correlating with the generation of a Th2 and Th1 immune response, respectively (20, 21). Surprisingly, we found that TSLPR signaling had no detectable impact on H. polygyrus-induced Th2 polarization and only a minor impact on N. brasiliensis-induced CD4⁺ T cell cytokine production. In addition, TSLPR signaling had no impact on Th2 memory responses and did not alter the ability of mice to expel either helminth after secondary infection. In contrast, TSLPR signaling was necessary to prevent IL-12p40 production after T. muris infection, and lack of TSLPR signaling led to impaired protective Th2 responses. Secreted products from H. polygyrus and N. brasiliensis, but not T. muris, were found to modulate DC function in vitro, such that these cells were refractory to LPS-induced production of the proinflammatory cytokine IL-12p40. These data indicate that particular helminths can directly modulate host DC to suppress IL-12p40 production and thus render TSLP redundant for the development of Th2 immune responses.     

Th1/Th2 cells in patients with multiple myeloma

Multiple myeloma (MM) is a lymphoproliferative disorder that is characterized by a proliferation of clonal B cells in various stages of maturation that then infiltrate the bone marrow. MM has been reported to accompany various T cell abnormalities including quantitative and functional defects of CD4+ and CD8+ T cells. Recently, immunotherapy such as dendritic cell therapy, vaccination therapy, and anti-tumor antibody therapy, has been attempted in patients with MM. To develop more effective immunotherapy for patients with MM, further studies are required to identify the immunological abnormalities, especially in T cells, associated with MM. The T helper 1 (Th1) and T helper 2 (Th2) cells are characterized by distinct cytokine production patterns. The Th1 cells produce interferon gamma and interleukin-2 (IL-2), and are involved in cell-mediated immunity. The Th2 cells produce IL-4 and promote humoral immunity by stimulating antibody production, particularly IgE responses. Furthermore, Th1 and Th2 cells have been found to cross-regulate each other's development. The Th1/Th2 combination has an important role in immune response to many disorders including infection, autoimmune diseases, and malignancies. In this review, we report a Th1/Th2 imbalance in cases of MM, and discuss the relationship between T cell abnormalities and the pathology of MM.