The Th1 and Th2 cytokines IFN-γ and IL-4 antagonize the inhibition of monocyte IL-1 receptor antagonist by glucocorticoids: involvement of IL-1

Monocytes express IL-1 and IL-1 receptor antagonist (IL-1Ra) in response to lipopolysaccharide (LPS). IL-1 self-induction contributes to the increase in IL-1 following LPS stimulation. LPS-stimulated IL-1 and IL-1Ra production are inhibited by glucocorticoids. In the present work we examined the regulation of IL-1Ra by Th1 cytokine IFN-γ, Th2 cytokine IL-4, glucocorticoids and IL-1 in human monocytes. We demonstrate that IL-1 contributes to LPS-induced IL-1Ra expression as shown by IL-1 blockade in LPS-stimulated monocytes using a specific anti-IL-1β antibody or recombinant IL-1Ra. Glucocorticoids inhibited IL-1β-stimulated IL-1Ra mRNA expression and protein production. Glucocorticoids inhibited both IL-1-mediated and non-mediated LPS stimulation of IL-1Ra expression. Both IFN-γ and IL-4 reversed the inhibitory effect of glucocorticoids on IL-1Ra expression and secretion. The effect of IFN-γ was blocked by pretreatment of monocytes with an anti-IL-1β blocking antibody, whereas the effect of IL-4 could not be blocked, demonstrating that IFN-γ acts through a mechanism dependent on endogenous IL-1 production, whereas IL-4 acts through an IL-1-independent one. Consistent with this finding, IFN-γ (but not IL-4) failed to reverse the inhibitory effect of glucocorticoids when stimulated by IL-1, and only IL-4 combined with IL-1 showed synergism resulting in an increase in IL-1Ra production. The differential regulation and involvement of IL-1 in the expression of IL-1Ra by IFN-γ, IL-4 and glucocorticoids sets the level of monocyte responsiveness during the Th1 or Th2 responses.     

Circulating Tumor Necrosis Factor (TNF)-α in Normally Cycling Women and Patients with Premature Ovarian Failure and Polycystic Ovaries

PROBLEM : The purpose of this study was to investigate the levels of tumor necrosis factor (TNF)-α in sera of infertile patients having premature ovarian failure (POF) and polycystic ovaries (PCO), and to compare the levels with those in age-matched normally cycling women. METHOD : Levels of TNF-α, luteinizing hormone (LH), follicle-stimulating hormone (FSH), and estradiol (E2) were measured in the sera of infertile and normal women by the enzyme linked immunosorbent assay (ELISA), fluorescent immunoassay and radioimmunoassay (RIA), respectively. Multiple groups comparisons were performed using Dunnet's test. Post-hoc analysis was performed using a Tukey-Kramer test. P < 0.05 was considered statistically significant. RESULTS : TNF-α levels were significantly (P = 0.003 to < .0001) lower in the sera of patients with POF compared to sera of controls and patients with PCO. CONCLUSIONS : TNF-α may have a role in ovarian function. Derangement in follicular development, luteal function and atresia results in a change of circulating TNF-αa levels.     

Dynamic changes of apoptosis-inducing ligands and Th1/Th2 like subpopulations in Hantaan virus-induced hemorrhagic fever with renal syndrome

The expression of the apoptosis-inducing ligands, TNF-alpha, FasL and TRAIL on peripheral blood mononuclear cells (PBMC) and the levels of their soluble form (TNF-alpha, sFasL and sTRAIL) in plasma from 40 hemorrhagic fever with renal syndrome (HFRS) patients as well as 26 healthy blood donors were determined by flow cytometry (FCM) analysis and sandwich ELISA, respectively. The status of Th1, Th2, Tc1 and Tc2 subsets in PBMC was evaluated by intracellular cytokine staining and FCM. Compared to controls, the expression of membrane bound FasL and TRAIL was up-regulated on surface of PBMC isolated from the HFRS patients, particularly on CD8+ T lymphocytes. The levels of TNF-alpha, sFasL and sTRAIL in plasma from the HFRS patients in the acute phase increase 4.7-fold, 6.0-fold and 1.8-fold, respectively, over those from the healthy donors. The percentage of Th1, Tc1 and Tc2 subsets in PBMC from the patients also increased significantly compared with those from healthy donors. These results indicate that dynamic changes occurred in both the membrane bound and soluble forms of apoptosis-inducing ligands (FasL, TRAIL and TNF-alpha) and proportions of Th1 and CTL in HFRS patients increased. Both factors may play an important role in the etiology of Hantaan virus infection in humans.     

Expression of macrophage inflammatory protein (MIP)-1α, MIP-1β, and RANTES genes in lymph nodes from HIV+ individuals: correlation with a Th1-type cytokine response

The in vivo response of the immune system after HIV infection in regard to cytokine production and C-C chemokine synthesis is not well known. Here we have analysed cytokine and chemokine mRNA production in lymph nodes with follicular hyperplasia (FHLN) of HIV-infected patients by in situ hybridization using anti-sense mRNA probes. The synthesis of mRNAs for interferon-gamma (IFN-γ), IL-12p35, IL-12p40, IL-4, and for the C-C chemokines RANTES, MIP-1α, and MIP-1β was compared with that of lymph nodes from non-infected individuals to define HIV-specific events. Only few cells expressing IFN-γ, RANTES, MIP-1α, and MIP-1β mRNAs were detectable in the T-dependent area of lymph nodes from HIV-negatives. In contrast, in FHLN from HIV⁺ patients a high number of IFN-γ, RANTES, MIP-1α, and MIP-1β mRNA-containing cells were detectable. Remarkably, only single individual IL-12p35 mRNA-producing cells were present in the T-dependent area from both HIV⁺ and HIV^? lymph nodes. Furthermore, the low number of IL-12p40 mRNA-expressing cells did not differ between HIV⁺ and HIV^? lymph nodes. This indicates that IFN-γ is expressed independently of IL-12, possibly by a direct T cell-mediated reaction. IL-4 mRNA-producing cells were hardly detectable in infected and control lymph nodes. The same findings were made in a limited number of samples from patients with advanced disease. Thus, these results demonstrate that a high IFN-γ production is accompanied by a strong expression of MIP-1α, MIP-1β, and RANTES in the lymph node after HIV infection. This favours the idea that a Th1-type immune response correlates with a preferential production of C-C chemokines in FHLN of HIV⁺ patients.     

Soluble IL-2 receptor and tumour necrosis factor-alpha in plasma of haemophilia patients infected with HIV.

We measured plasma concentrations of soluble receptors for IL-2 (sIL-2R) and tumour necrosis factor-alpha (TNF-alpha) in 149 haemophilia patients. Soluble IL-2R levels were elevated in 37% of 62 HIV-seronegative patients (mean 570 +/- 27 U/ml versus 361 +/- 17 U/ml in the control group, P less than 0.0001), in 78% of 68 HIV-seropositive patients (928 +/- 49 U/ml, P less than 0.0001), and in 95% of 19 AIDS/ARC patients (1578 +/- 199 U/ml, P less than 0.0001 compared with controls and with HIV-seronegative patients; P less than 0.005 compared with HIV-seropositive asymptomatic patients). A negative correlation was observed between sIL-2R, relative and absolute numbers of CD4+ cells (P less than 0.0001), and CD4/CD8 ratios (P less than 0.0001). There was also a negative correlation between sIL-2R in plasma and the cellular expression of IL-2R (P less than 0.001). We found a significant association of sIL-2R and plasma neopterin (P less than 0.0001). With progression of the disease from HIV-seronegative to seropositive without symptoms and to full manifestation of AIDS/ARC, sIL-2R plasma levels increased. The highest levels were found at the time of diagnosis of AIDS/ARC, but the levels decreased again during the following 18 months. Eight per cent of HIV-seronegative patients, 32% of HIV-seropositive patients, and 24% of patients with AIDS/ARC had increased plasma TNF-alpha. We conclude that sIL-2R and TNF-alpha plasma levels are elevated in HIV-infected haemophilia patients and that sIL-2R is a marker for disease progression from asymptomatic HIV-seropositive to AIDS/ARC.     

The potential impact of CD4+ T cell activation and enhanced Th1/Th2 cytokine ratio on HIV-1 secretion in the lungs of individuals with advanced AIDS and active pulmonary infection

Bronchoalveolar lavage fluid (BALF) provides a source of mucosal CD4(+) T cells. We investigated the physiological properties of T lymphocytes from BALF and blood and their role on the dynamic of HIV-1 replication among AIDS patients with active lung infections. Pulmonary CD4(+) T cells consist mainly of effector memory cells (CD45RO(+) and CCR7(-)) with increased expression of activation markers (HLA-DR(+) and CD69(+)) when compared to the blood counterpart. We observed a high frequency of BALF cells capable of secreting HIV-1-Ags suggesting that the local lung environment may support favorable conditions for CD4(+) T lymphocytes harboring HIV-1 DNA to initiate the viral cycle. Nevertheless, the high number of IFN-γ-producing cells and the predominance of Th1 immune response in the lung could limit the secretion of HIV-1 RNA. In conclusion, the capacity of activated CD4(+) T cells to produce HIV-1 is driven by both the level and quality of cellular activation in the lung.     

Adjuvant-Induced Improvement of Glucose Intolerance in Type 2 Diabetic KK-Ay Mice Through Interleukin-1 and Tumor Necrosis Factor-α

We reported that administration of complete Freund's adjuvant (CFA) improved glucose tolerance test (GTT) results in obese diabetic KK-Ay mice. In this study, we investigated its mechanism. An injection with CFA remarkably improved GTT for more than a week in KK-Ay mice, although insulin response was not changed compared with saline controls. The hypoglycemic effect of insulin was significantly, but partially, potentiated in the CFA-treated mice compared with the controls, suggesting that CFA stimulated insulin-mediated and non-insulin-mediated glucose disposal. Improvement in the GTT with CFA was partially transferable to nontreated mice by peritoneal exudative cells, but not spleen or lymph node cells. Pretreatment with anti-interleukin (IL)-1α and -1β antibodies or anti-tumor necrosis factor (TNF)-α antibody significantly abrogated the improvement in the GTT with CFA. The results indicate that CFA-induced improvement in glucose intolerance in KK-Ay mice was mediated at least by IL-1 and TNF-α.     

Enhanced synthesis of cytokines by peripheral blood monocytes cultured in the presence of autoantibodies against U1-ribonucleoprotein and/or negatively charged molecules: implication in the pathogenesis of pulmonary hypertension in mixed connective tissue disease (MCTD).

An attempt was made to determine whether addition of purified autoantibodies against U1-ribonucleoprotein (RNP) and negatively charged molecules (cardiolipin and double-stranded (ds) DNA) to cultures of peripheral blood monocytes could enhance the synthesis of cytokines in patients with MCTD and normal healthy volunteers. It was found that: (i) at the baseline, levels of cytokines such as IL-1 alpha, IL-1 beta and IL-6 extracellularly released by or associated with monocytes were significantly higher in MCTD patients than in normal subjects; (ii) addition of antibodies against U1-RNP to cultures of MCTD monocytes resulted in a significant overall increase of the released and cell-associated IL-1 alpha, IL-1 beta and IL-6. On the other hand, addition of antibodies against cardiolipin or dsDNA to cultures of MCTD monocytes resulted in a significant increase of released and/or cell-associated IL-1 alpha and IL-1 beta; (iii) addition of these autoantibodies to cultures of normal monocytes resulted in a significant overall increase of released and cell-associated IL-1 alpha, IL-1 beta and IL-6. The extent of enhancement of cytokines released by or associated with monocytes was greater in normal subjects than in MCTD patients; (iv) a F(ab')2 preparation of autoantibodies against U1-RNP also enhanced the level of released and cell-associated IL-1 alpha. Our findings that both autoantibodies against U1-RNP and negatively charged molecules were able to enhance the synthesis of cytokines by monocytes suggest that these autoantibodies might cause derangement of endothelial cells and lead to proliferative vasculopathy, which is a characteristic of pulmonary hypertension in MCTD.     

Perinatal infection by human immunodeficiency virus type 1 (HIV-1): relationship between proviral copy number in vivo, viral properties in vitro, and clinical outcome.

Human immunodeficiency virus type 1 (HIV-1) isolates from 25 perinatally HIV-1 infected children were classified according to their capacity to replicate in vitro as rapid (R), intermediate (S/R) and slow (S) variants. R-type viruses replicated on peripheral blood mononuclear cells (PBMCs) and grew better in T-lymphoid cells, even though 9 out of 12 isolates also maintained tropism for monocytoid cells. The S/R-type isolates replicated efficiently after several days of culture, while the S-type viruses displayed only a low and transient replication activity; however, both S/R- and S-type isolates exerted viral transactivation activity in an indicator monocytoid cell line. Replication patterns in vitro were significantly associated in vivo with the number of HIV-1 copies in PBMCs as determined by polymerase chain reaction: in children with R-type isolates, the number of HIV-1 proviral DNA molecules/10(5) PBMCs ranged from 62 to 571, and in children with S/R and S isolates the range was 5-43. Seven children had severe symptomatic HIV-1 infection, and in all an R-type virus was identified; 18 children had no or only mild symptoms, and among these, S-, S/R-, and R-type isolates were found in 5, 8, and 5 cases, respectively. Besides demonstrating HIV-1 variability in perinatal infection, these findings suggest that R-type virus might be a prerequisite for disease progression.     

Significance of IL-1β and IL-1 receptor antagonist (IL-1Ra) in bronchoalveolar lavage fluid (BALF) in patients with diffuse panbronchiolitis (DPB)

We evaluated the effect of erythromycin therapy on pulmonary function tests and the airway inflammatory response of patients with DPB. The number of neutrophils in BALF obtained from DPB patients was significantly higher than that of healthy volunteers. Treatment with erythromycin (600 mg/day for 12·9 ± 9·5 months (mean ±s.d.)) significantly reduced the total number of cells and neutrophils in the airway, and significantly improved pulmonary function tests. The levels of IL-1β and IL-8 were significantly higher in DPB compared with healthy volunteers (P < 0·05, P < 0·05, respectively). IL-1 Ra in patients is considered to have a weak inhibitory activity for IL-1β, with approximately five-fold concentration of IL-1β compared with that in healthy volunteers (approx. nine-fold concentration of IL-1β). Erythromycin therapy significantly reduced these cytokines to levels comparable to those of healthy volunteers, and produced a trend toward reduction in the level of IL-1Ra in BALF. The level of IL-1β correlated significantly with the concentration of neutrophils in BALF (r = 0·72, P < 0·01), as well as with the level of IL-1Ra (r = 0·688, P < 0·05) and IL-8 (r = 0·653, P < 0·05). A nearly significant or significant correlation was observed between the concentration of neutrophils and levels of IL-1Ra or IL-8 in BALF (r = 0·526, P = 0·053 or r = 0·776, P < 0·01, respectively). There was also a significant relationship between FEV, and the concentration of neutrophils in BALF (r = 0·524, P < 0·05). Our results suggest that the relative amounts of IL-1β and IL-1Ra or IL-8 may contribute, at least in part, to the neutrophil-mediated chronic airway inflammation in patients with chronic airway disease, and long-term erythromycin therapy may down-regulate the vigorous cycle between the cytokine network and neutrophil accumulation, with resultant reduction of neutrophil-mediated inflammatory response.     

Lineage and signal strength determine the inhibitory effect of transforming growth factor beta1 (TGF-beta1) on human antigen-specific Th1 and Th2 memory cells

TGF-beta1 is a pleotrophic cytokine playing an important role in immune regulation. The impact of TGF-beta1 on immune function is determined by the cell type and the microenvironment. CD4+ T cells exemplify this, by responding to TGF-beta1 in heterogeneous ways based on their level of maturation and state of differentiation. TGF-beta1 leads to suppression of proliferation and cytokine production of naive T cells and influences the outcome of T cell differentiation. In mice, the response of memory T cells to TGF-beta1 is determined by the lineage of the cells. TGF-beta1 causes decreased proliferation of Th1 cells but has little effect on the proliferation of Th2 cells. Here we examined the effect of TGF-beta1 on human Th1 and Th2 memory T cells and show that proliferation of Th1 clones are inhibited by TGF-beta1, whereas Th2 cells are not. Furthermore the sensitivity of individual Th1 clones to TGF-beta1 is linked to the level of activation achieved in culture, but these differences cannot be explained by T cell receptor (TCR) affinity alone. Together this demonstrates that the human T cell response to TGF-beta1 is determined by the environment in which an immune response takes place and the previous immune experience of the cells involved.     

Kinetics of soluble tumour necrosis factor (TNF)-alpha receptors and cytokines in the early phase of treatment for chronic hepatitis C: comparison between interferon (IFN)-alpha alone, IFN-alpha plus amantadine or plus ribavirin

We have previously studied the effect of three different treatment regimens with interferon (IFN)-alpha alone or in combination with amantadine or ribavirin on viral kinetics in the first month of therapy. To understand the regulation of cytokine immune response during early inhibition of HCV replication, we analysed the longitudinal profile of proinflammatory markers (soluble TNFRs), of type 1 cytokines [IFN-gamma and interleukin (IL-12)], and of a type 2 cytokine (IL-10). Twenty-two chronic hepatitis C patients received daily therapy for 6 months. Sera were collected at baseline, at 6, 12, 24, 30 and 48 h and at the 3rd, 7th, 15th and 30th days of treatment. All cytokines and receptors were evaluated by enzyme linked immunosorbent assay (ELISA). At baseline, a correlation was found between the two soluble TNFRs (P < 0.0001) and between the soluble TNFRs and ALT levels (P < 0.003), as shown previously. Regardless of the type of treatment, lower levels of soluble TNFR-p75 were present from day 3 in patients who had significant virus decay at day 30 (P < 0.01). Baseline IL-10 levels correlated with TNFR-p75 (P < 0.01) and with treatment response (P < 0.05) and a significant IL-10 reduction from baseline was observed from day 3 among responders, irrespective of the type of treatments (P < 0.05). IL-12 and IFN-gamma levels did not differ according to treatment or outcome. These findings suggest a pivotal role for IL-10 in orchestrating the antiviral immune response. Its early decline can favour the shift from a Th2 to a Th1 immune response, which has been shown to be associated with a long-term virological response to treatment.     

Immune Suppression and Th1/Th2 Balance in Pregnancy Revisited: A (Very) Personal Tribute to Tom Wegmann

PROBLEM: The paradigm of local suppression necessary to understand the survival of the fetal allograft is often compared with the host-tumor relationship. METHODS: We investigated two components of local immune suppression: placenta-induced immunosuppression, which is mediated at least in part by a soluble factor of low molecular weight that can induce anergy in lymphocytes, and interleukin-10 (IL-10). RESULTS: We show that enhancement of IL-10 production in the decidua and placenta after alloimmunization requires the presence of Asialo GM1+ cells. Placenta-induced immunosuppression is linked with defects in phosphorylation of some components of the T cell receptor. CONCLUSION: NK cells could be in fact regulatory cells pushing maternal immune response toward a Th2 profile, beneficial for fetal survival, or toward a Th1 type of immune response, which acts in synergy. Modulation of TcR may represent a new mechanism for maternal-fetal tolerance.     

Chemically modified tetracycline (CMT)-3 inhibits histamine release and cytokine production in mast cells: possible involvement of protein kinase C

Objective: To find novel inhibitors of mast cell function we have studied the effect of a potent, non-antimicrobial, chemically modified tetracycline, CMT-3 or COL-3, on key functions of mast cells.Methods and Results: In the presence of 25 μM CMT-3, the 48/80-induced histamine release from rat serosal mast cells was inhibited significantly, to 43.0 ± 7.3% of control. Similarily, the activation-induced secretion of TNF-α and IL-8 by HMC-1 cells were decreased in the presence of 25 μM CMT-3 to 13.5 ± 4.1% and 9.7 ± 1.1% of control, respectively. CMT-3 did not cause intracellular accumulation of TNF-α but instead it reduced the expression of TNF-α mRNA in HMC-1 cells. Moreover, CMT-3 was found to significantly inhibit the protein kinase C (PKC) activity with IC₅₀ value of 31 μM. CMT-3 inhibited effectively both human recombinant PKCalpha and PKCdelta isoforms. In comparison to doxycycline, CMT-3 was more effective as an inhibitor of both cytokine production and PKC activity.Conclusions: Considering the central role of PKC in mast cell activation, PKC inhibition could, at least partially, explain the observed inhibitory effects of CMT-3. The inhibition of the key proinflammatory functions of mast cells by CMT-3 suggests its potential clinical usefulness in the treatment of allergic and inflammatory disorders.Received 18 February 2005; returned for revision 7 March 2005; accepted by A. Falus 21 April 2005     

CD8+ T cell responses to human immunodeficiency viruses type 2 (HIV-2) and type 1 (HIV-1) gag proteins are distinguishable by magnitude and breadth but not cellular phenotype

The mechanisms underlying the relatively slow progression of human immunodeficiency virus type 2 (HIV-2) compared with HIV-1 infection are undefined and could be a result of more effective immune responses. We used HIV-2 and HIV-1 IFN-gamma enzyme-linked immunospot assays to evaluate CD8(+) T cell responses in antiretroviral-naive HIV-2- ('HIV-2(+)') and HIV-1-infected ('HIV-1(+)') individuals. Gag-specific responses were detected in the majority of HIV-2(+) and HIV-1(+) subjects. Overlapping gag peptide analysis indicated a significantly greater magnitude and breadth of responses in the HIV-1(+) cohort, and this difference was attributable to low responses in HIV-2(+) subjects with undetectable viral load (medians 2107 and 512 spot-forming units per 10(6) PBMC, respectively, p=0.007). We investigated the phenotype of viral epitope-specific CD8(+) T cells identified with HLA-B53- and HLA-B58-peptide tetramers (8 HIV-2(+), 11 HIV-1(+) subjects). HIV-2-specific CD8(+) T cells were predominantly CD27(+) CD45RA(-), and only a minority expressed perforin. The limited breadth and low frequency of CD8(+) T cell responses to HIV-2 gag in aviremic HIV-2(+) subjects suggests that these responses reflect antigen load in plasma, as is the case in HIV-1 infection. Immune control of HIV-2 does not appear to be related to the frequency of perforin-expressing virus-specific CD8(+) T cells.     

Modulation of the expression of M150 on macrophages by Th1/Th2 cytokines and co-stimulatory molecules CD40, B7-1, B7-2 and ICAM-1

M150 is an 150-kDa protein associated with the surface of macrophages and is responsible chiefly for the activation of Th1 cells. It is a unique subset of the lysosome-associated membrane protein-1 glycoprotein and its co-stimulatory activity depends on its post-translational modification, which has a distinct glycosylation pattern restricted to macrophages. In the present study, we have observed that M150 is expressed constitutively on peritoneal but not splenic macrophages isolated from mice of different genetic backgrounds: Balb/c, C57BL/6 and C3He. However, M150 was expressed not only on peritoneal but also on splenic macrophages of non-obese diabetic (NOD) mice. Expression on splenic macrophages was induced by culture with lipopolysaccharide (LPS). Expression could also be significantly up-regulated by interferon (IFN)-gamma and granulocyte-macrophage colony stimulating factor (GM-CSF) but was inhibited by interleukin (IL)-10; IL-4 exhibited no effect. Further, cross-linking of B7-2, CD40, ICAM-1 but not B7-1 enhanced the level of M150 significantly. IFN-gamma and GM-CSF acted synergistically with CD40. The significance of these findings is that cytokines IFN-gamma, GM-CSF and IL-10 and the co-stimulatory molecules B7-2, CD40 and ICAM-1 can regulate the expression of M150 on macrophages.     

Elevated preconception CD56+ 16+ and/or Th1:Th2 levels predict benefit from IVIG therapy in subfertile women undergoing IVF

Citation Winger EE, Reed JL, Ashoush S, El‐Toukhy T, Ahuja S, Taranissi M. Elevated preconception CD56⁺16⁺ and/or Th1:Th2 levels predict benefit from IVIG therapy in subfertile women undergoing IVF. Am J Reprod Immunol 2011; 66: 394–403 Problem We sought to answer two questions: First, is there a group of patients who benefit from intravenous immunoglobulin (IVIG) in IVF? Second can this group of patients be identified by preconception blood testing? Method of study A total of 202 IVF cycles in subfertile women were divided into four groups. Group I: 62 cycles with preconception Th1:Th2 ratio and/or % CD56⁺ cell elevation using IVIG; Group II: 27 cycles with similar Th1:Th2 and/or % CD56⁺ cell elevation not using IVIG; Group III: 71 cycles with normal Th1:Th2 and/or % CD56⁺ cell levels using IVIG; Group IV: 42 cycles with normal Th1:Th2 and % CD56⁺ levels not using IVIG. These groups were similar with regard to patient age, diagnosis, and past failure history. Results The implantation rate (number of gestational sacs per embryo transferred, with an average of two embryos transferred per cycle) was 45% (55/123), 22% (12/54), 54% (75/139), and 48% (40/84) for Groups I–IV, respectively. The clinical pregnancy rate (fetal heart activity per IVF cycle started) was 61% (38/62), 26% (7/27), 69% (49/71), and 71% (30/42), respectively. The live birth rate was 58% (36/62), 22% (6/27), 61% (43/71), and 71% (30/42), respectively, and the live birth per embryo transferred was 40% (49/123), 13% (7/24), 43% (60/139), and 48% (40/84), respectively. There was a significant improvement in implantation, clinical pregnancy, live birth rate and live birth rate per embryo transferred for Group I versus Group II (P = 0.0032, 0.0021, 0.0017, and 0.0002, respectively) and for Group II versus Group IV (P = 0.0021, 0.0002, <0.0001 and <0.0001, respectively). There was no significant difference in success rates between Groups I and III (P = 0.085, 0.23, 0.45, 0.34, respectively) and between Groups III and IV (P = 0.22, 0.48, 0.17, 0.31, respectively). Conclusion In subfertile women with preconception Th1:Th2 and/or % CD56⁺ cell elevation, IVF success rates are low without IVIG therapy but significantly improve with IVIG therapy. In patients with normal Th1:Th2 and normal CD56⁺ cell levels, IVF success rates were not further improved with IVIG therapy. IVIG may be a useful treatment option for patients with previous IVF failure and preconception Th1:Th2 and/or NK elevation. Preconception immune testing may be a critical tool for determining which patients will benefit from IVIG therapy. Prospective controlled studies (preferably double‐blind, stratified, and randomized) are needed for confirmation.