Risk of lymphoma subtypes after solid organ transplantation in the United States.

BACKGROUND: Solid organ transplant recipients have high risk of lymphomas, including non-Hodgkin lymphoma (NHL) and Hodgkin lymphoma (HL). A gap in our understanding of post-transplant lymphomas involves the spectrum and associated risks of their many histologic subtypes. METHODS: We linked nationwide data on solid organ transplants from the US Scientific Registry of Transplant Recipients (1987-2008) to 14 state and regional cancer registries, yielding 791 281 person-years of follow-up for 19 distinct NHL subtypes and HL. We calculated standardised incidence ratios (SIRs) and used Poisson regression to compare SIRs by recipient age, transplanted organ, and time since transplantation. RESULTS: The risk varied widely across subtypes, with strong elevations (SIRs 10-100) for hepatosplenic T-cell lymphoma, Burkitt's lymphoma, NK/T-cell lymphoma, diffuse large B-cell lymphoma, and anaplastic large-cell lymphoma (both systemic and primary cutaneous forms). Moderate elevations (SIRs 2-4) were observed for HL and lymphoplasmacytic, peripheral T-cell, and marginal zone lymphomas, but SIRs for indolent lymphoma subtypes were not elevated. Generally, SIRs were highest for younger recipients (<20 years) and those receiving organs other than kidneys. CONCLUSION: Transplant recipients experience markedly elevated risk of a distinct spectrum of lymphoma subtypes. These findings support the aetiologic relevance of immunosuppression for certain subtypes and underscore the importance of detailed haematopathologic workup for transplant recipients with suspected lymphoma.

The multicenter AIDS Cohort Study, 1983 to .

The Multicenter AIDS Cohort (MACS), initiated in 1983 at the Johns Hopkins School of Public Health, the University of Pittsburgh School of Public Health, Northwestern University School of Medicine, and the UCLA School of Public Health, continues to conduct studies and publish key papers on the natural history of untreated and treated HIV infection in 6972 men-who-have-sex-with-men. Through May 2011, 1,490,995 specimens have been collected, 86,883 person-years of data accrued and 1195 scientific papers published in international journals.

Frequencies of the separate human B cell subsets activatable to Ig secretion by Epstein-Barr virus and pokeweed mitogen.

We have developed a microculture system suitable for limiting dilution analysis of Epstein-Barr virus (EBV)- and pokeweed mitogen (PWM)-induced activation of immunoglobulin secretion by human B cells. It was found that exogenous filler cells were not required to obtain optimal EBV-induced B cell precursor frequency (PF) estimates, although filler T cells were required for optimal PWM activation. In fact, when autologous T cells were used as filler cells, a marked decrease in the EBV-induced IgM PF was noted. Treatment of the T cells with cyclosporin A partially eliminated, and irradiation of the T cells completely eliminated, this decrease. The calculated PF of B cells activated by EBV was from 1/290 to 1/3,700 for IgM, and from 1/920 to 1/3,250 for IgG secretion. PWM activated from 1/140 to 1/3,200 B cells to IgM secretion. The results of experiments in which EBV and PWM were mixed, indicated that these two polyclonal activators operated on different B cell subpopulations. Therefore, both these agents seem to activate small, discrete subpopulations of human peripheral blood B cells to Ig secretion.

Oncostatin M as a potent mitogen for AIDS-Kaposi's sarcoma-derived cells.

Oncostatin M, a cytokine produced by activated lymphoid cells, regulates the growth and differentiation of a number of tumor and normal cells. In contrast to its effects on normal endothelial and aortic smooth muscle cell cultures, Oncostatin M was a potent mitogen for cells derived from acquired immunodeficiency syndrome-related Kaposi's sarcoma (AIDS-KS). After exposure to Oncostatin M, AIDS-KS cells assumed a spindle morphology, had an increased ability to proliferate in soft agar, and secreted increased amounts of interleukin-6. Oncostatin M RNA and immunoreactive Oncostatin M protein were found in AIDS-KS-derived cell isolates. These results suggest that Oncostatin M may play a role in the pathogenesis of AIDS-KS.

Brief report: Circulating markers of fibrosis are associated with immune reconstitution status in HIV-infected men.

INTRODUCTION: Lymphoid tissue fibrosis may contribute to incomplete immune reconstitution on antiretroviral therapy (ART) via local CD4+ T lymphocyte (CD4) depletion. Hyaluronic acid (HA) increases with fibrotic burden. CXCL4 concentrations increase in response to pro-fibrotic stimuli, but lower CXCL4 concentrations in HIV-infected individuals may reflect successful immune evasion by HIV. We investigated relationships between circulating HA and CXCL4 concentrations and immune reconstitution on ART in HIV-infected Multicenter AIDS Cohort Study participants. METHODS: HIV-infected men on ART for >1 year with cryopreserved plasma samples and suppressed post-ART HIV-1 RNA were included. Men with post-ART CD4 <200 cells/mm3 were defined as immunologic non-responders (n = 25). Age-/race-matched men with post-ART CD4 >500 cells/mm3 served as controls (n = 49). HA and CXCL4 concentrations were measured via ELISA. RESULTS: Median pre-ART CD4 was 297 cells/mm3 for non-responders vs 386 cells/mm3 for controls. Median post-ART CD4 was 141 cells/mm3 for non-responders and 815 cells/mm3 for controls. HIV infection duration was 23 years, with median time on ART 13 years for non-responders vs 11 years for controls. Pre-ART HA and CXCL4 concentrations did not vary by eventual immune reconstitution status. Post-ART HA concentrations tended to be higher (85 vs 36 ng/mL, p = 0.07) and CXCL4 concentrations were lower (563 vs 1459 ng/mL, p = 0.01) among non-responders. Among men with paired pre-/post-ART samples, non-responders had greater HA increases and CXCL4 decreases than controls (HA: 50 vs 12 ng/mL, p = 0.04; CXCL4: -1258 vs -405 ng/mL, p = 0.01). CONCLUSIONS: Higher circulating concentrations of HA and lower concentrations of CXCL4 are associated with failure of immune reconstitution on ART.

Constitutive production of interleukin 6 by ovarian cancer cell lines and by primary ovarian tumor cultures.

We examined the production and utilization of interleukin 6 (IL-6), a multifunctional cytokine with diverse biological effects, by both ovarian cancer cell lines and primary ovarian tumor cultures. We have found that epithelial ovarian cancer cell lines (CAOV-3, OVCAR-3, and SKOV-3) constitutively produce varying amounts of IL-6. This molecule is biologically active as determined by the proliferation of an IL-6-dependent hybridoma cell line, MH60.BSF-2, and is detectable by an IL-6 enzyme-linked immunosorbent assay. By cytoplasmic immunoperoxidase staining, greater than 98% of the cells produce at least some IL-6, with variation in the staining intensity between individual cells. The ovarian cancer cell-produced protein has a molecular weight of approximately 24,000, and exhibits some molecular weight heterogeneity, with Mr 27,000 and 28,000 minor forms of IL-6. The levels of IL-6 produced by ovarian cancer cells can be modulated by other inflammatory cytokines, such as tumor necrosis factor-alpha, interleukin-1 beta, and interferon-gamma. Our results suggest that IL-6 is not an autocrine growth factor for these established ovarian tumor cell lines, because the addition of either exogenous IL-6 or antibodies to IL-6 did not affect the cellular proliferation of the cell lines. We also found significant levels (greater than 3 ng/ml) of IL-6 in ascitic fluids of ovarian cancer patients and in the supernants of primary cultures from freshly excised ovarian tumors. The production of IL-6 by epithelial ovarian cancer cells may prove to be a useful diagnostic tool and aid in investigation of the host immune response to ovarian cancer.

Resistance of human ovarian cancer cells to tumor necrosis factor and lymphokine-activated killer cells: correlation with expression of HER2/neu oncogenes.

Since overexpression of HER2/neu oncogenes in breast cancer cells is associated with resistance to the cytotoxic effect of tumor necrosis factor (TNF), we investigated whether this correlation also existed for ovarian cancer targets. Nine continuously cultured human ovarian cancer lines were studied and compared to 3 breast cancer lines. Three of the ovarian and 1 breast cancer line demonstrated amplified HER2/neu genes by Southern analysis, increased HER2/neu RNA by Northern analysis, and marked immunoperoxidase staining for HER2/neu protein. The other 8 lines contained unamplified genes and undetectable RNA and protein. All 4 overexpressed lines were relatively resistant to the cytotoxic effects of TNF. Interestingly, they were also resistant to lymphokine-activated killer cells. In contrast, 7 of 8 nonexpressed lines showed sensitivity to TNF and all 8 were sensitive to lymphokine-activated killer cells. There was no difference in sensitivity to lysis by hydrogen peroxide or peptide defensins between over- and nonexpressed lines. These data indicate that expression of HER2/neu oncogenes may impart a proliferative advantage in tumor cells due to induction of resistance to several different cytotoxic mechanisms.

Human herpesvirus 8-encoded interleukin 6 activates HIV-1 in the U1 monocytic cell line.

OBJECTIVE: Human herpesvirus 8 (HHV-8) encodes a viral interleukin 6 (vIL-6) which is structurally and functionally similar to human interleukin 6 (hIL-6). Since hIL-6 has been shown to upregulate the expression of HIV-1, the objectives of this study were to examine the ability of vIL-6 to upregulate HIV-1, and to determine the interactions of this virokine (viral cytokine) with the components of the interleukin 6 (IL-6) receptor complex. DESIGN AND METHODS: Recombinant HHV-8 vIL-6 (rvIL-6) was assayed for bioactivity in the IL-6-dependent cell line MH60.BSF2. HIV-1 p24 production by the U1 monocytic and ACH-2 T-cell lines, which are chronically infected with HIV-1, was used to assess the ability of vIL-6 to affect HIV-1 expression. hIL-6 and vIL-6 receptor utilization was determined by quantifying HIV-1 p24 production after neutralization of components of the IL-6 receptor complex, CD126'IL-6R' and CD130'gp130', on U1 cells with blocking antibodies. RESULTS: HHV-8 rvIL-6 was seen to have IL-6-like bioactivity in MH60.BSF2 cells, and readily upregulated HIV-1 p24 production in U1 monocytic cells, but not in ACH-2 T cells. The vIL-6 appeared to utilize the IL-6-specific component of the IL-6 signaling complex, CD126'IL-6R', in U1 cells. CONCLUSIONS: HHV-8 vIL-6 clearly has the potential to upregulate HIV-1 expression in monocytic cells, and therefore may play a role in AIDS pathogenesis in individuals infected with both viruses.

Serum soluble CD23 level correlates with subsequent development of AIDS-related non-Hodgkin's lymphoma.

The cytokine soluble CD23 (sCD23) has been shown to act as a B cell growth factor and to be elevated in serum prior to development of AIDS-related non-Hodgkin's lymphoma (AIDS NHL). To further characterize the elevation of serum sCD23 in AIDS NHL patients and investigate its potential as a diagnostic test, a matched case-control study of AIDS NHL (n = 101) was nested within the Multicenter AIDS Cohort Study. Serum sCD23 was measured in cases' and controls' serum specimens at three different time periods (0-6, 6-12, and 12-18 months) and CD4+ thresholds (0-99, 100-199, and 200-299 cells/microl) prior to the case's NHL diagnosis. Changes in serum sCD23 over time were examined in AIDS NHL cases relative to controls, and t tests were performed to determine whether cases' serum sCD23 exceeded that of controls at each time period and CD4+ threshold. Overall, cases' median serum sCD23 levels were approximately double those of controls. Serum sCD23 concentration was positively correlated with lymphocyte counts for both cases and controls. The difference in cases' and controls' serum sCD23 levels became greater as AIDS NHL diagnosis date approached: in the 18 months preceding the case's NHL diagnosis, serum sCD23 was stable in cases but dropped in controls. Although this difference was statistically significant (P < 0.05), it was not clinically significant. It is unlikely that serum sCD23 would make a useful test for AIDS NHL because the magnitude of the difference between cases and controls was small and there was no change in serum sCD23 in cases that would indicate disease.

Interleukin 6 and AIDS-associated Kaposi's sarcoma: a nested case control study within the Multicenter AIDS Cohort Study.

Since the beginning of the AIDS epidemic, there has been considerable research on the etiology of Kaposi's sarcoma (KS) among HIV-infected individuals. A number of studies have confirmed that HIV or HIV-encoded products can interact with human cells to induce the production of cytokines, including interleukin 6 (IL-6). In vitro observations have indicated that AIDS-KS cells can produce significant levels of IL-6 and also respond to this cytokine. Preliminary data suggested that IL-6 may be elevated among HIV-infected individuals that subsequently develop AIDS-KS. The objective of this study was to determine if elevated levels of IL-6 are associated with an increased incidence of AIDS-KS compared to other AIDS-defining illnesses such as opportunistic infections (OIs). Serum IL-6 levels were determined by ELISA in frozen sera collected from participants in the Multicenter AIDS Cohort Study (MACS) at 6 months prior to AIDS diagnosis, in 73 cases (AIDS-KS), and 152 controls (OI). Elevated IL-6 levels were more prevalent among men with AIDS-OI than those with AIDS-KS: crude odds ratio (OR), 0.4 (95% CI, 0.2-0.9). Models of multivariate logistic regression were used to study potential confounders. Sexual behavior variables did not seem to confound the association between IL-6 and AIDS-KS. The higher prevalence of IL-6 among controls could be explained by the association of higher levels of IL-6 with lower levels of CD4 T cell number. IL-6 may be a marker of severe immune dysfunction among HIV-infected individuals.

Effects of human papillomavirus-associated cells on human immunodeficiency virus gene expression.

OBJECTIVE: To examine the effects of soluble factors secreted by human papillomavirus (HPV)-associated cells on human immunodeficiency virus (HIV) expression. METHODS: Supernatants collected from cultured cervical biopsies and cervical cancer cell lines, and HPV-immortalized and normal keratinocytes were tested for the ability to induce HIV p24 production in two cell lines that contained latent HIV (the U1 monocytic line and the ACH-2 T cell line). Levels of HIV p24 were measured by enzyme-linked immunosorbent assay (ELISA). Culture supernatants were also assayed for the inflammatory cytokines interleukin 6, tumor necrosis factor, and interleukin 1 beta by ELISA. RESULTS: Supernatants from all epithelial cells tested upregulated HIV p24 expression in the U1 line but not in the ACH-2 cells. Only differentiated normal keratinocytes induced p24 production by ACH-2 cells. Neutralization of the cytokines, particularly interleukin 6, partially reduced the level of HIV-inducing activity in the culture supernatants. Additionally, cervical biopsies from HIV-infected women cultured in vitro also were able to induce HIV in U1 cells but not ACH-2 cells. CONCLUSIONS: Our results suggest that HPV infection of the cervix might influence HIV pathogenesis by inducing the production of immune and inflammatory factors that enhance HIV expression.

Detection of interleukin-6 in human follicular fluid.

OBJECTIVE: To determine if interleukin-6 (IL-6) is a normal constituent of human follicular fluid (FF) after ovarian hyperstimulation and to assess whether IL-6 levels differ in conditions associated with immunological causes of infertility. DESIGN: After ovarian hyperstimulation for an in vitro fertilization (IVF) treatment cycle, FF samples were obtained at the time of oocyte retrieval. SETTING: Referral center at a tertiary care hospital. PATIENTS: Thirty women referred for IVF, including 10 patients with significant titers (greater than 40%) of antisperm antibodies and 10 with pelvic endometriosis. Ten patients with tubal infertility without antisperm antibodies or endometriosis served as controls. MAIN OUTCOME MEASURES: Analysis of FF levels for IL-6 using both bioassay and immunoassay. RESULTS: Bioactive (range 0.32 to 32.2 U/mL) and immunoreactive (range 0.34 to 13.6 ng/mL) IL-6 levels were detected in FF of all subjects after ovarian hyperstimulation. Follicular fluid IL-6 levels were substantially higher (3 to 30-fold) than that reported in serum. There was no difference in the mean concentrations of IL-6 levels between patients with antisperm antibodies, endometriosis, or tubal infertility. CONCLUSIONS: Bioactive and immunoreactive IL-6 are present in human FF after ovarian hyperstimulation, supporting a potential autocrine or paracrine role within the follicular microenvironment.

Peritoneal fluid interleukin-6 in women with chronic pelvic pain.

OBJECTIVE: To determine the relationship between peritoneal fluid concentrations of interleukin-6 (IL-6) and chronic pelvic pain symptomatology in women with adhesions, endometriosis, or no obvious intraperitoneal pathology. DESIGN: Clinical research study. SETTING: Healthy volunteers in an academic research environment. PATIENT(S): Reproductive-aged women undergoing laparoscopy for the diagnosis of pelvic pain, infertility, or sterilization were selected. INTERVENTION(S): Peritoneal fluid was collected at the time of the laparoscopy and later assayed for IL-6. Subjects completed a pelvic pain questionnaire, and operative reports were used to obtain the underlying diagnosis. MAIN OUTCOME MEASURE(S): Interleukin-6 concentrations. RESULT(S): No correlation between the presence or absence of pelvic pain, findings of adhesions or endometriosis, and the concentration of peritoneal fluid IL-6 was observed. CONCLUSION(S): The cytokine IL-6 does not seem to play a role in the genesis of chronic pelvic pain in women with adhesions or endometriosis.

Interleukin 10: ability to minimize postoperative intraperitoneal adhesion formation in a murine model.

OBJECTIVE: To determine the ability of interleukin 10 (IL-10) to suppress postoperative intraperitoneal adhesion formation. DESIGN: Randomized, controlled trial. SETTING: University animal research facility. ANIMALS: Six-week-old Swiss Webster mice undergoing a standardized intraperitoneal operative procedure. INTERVENTIONS: Animals were randomized to "surgery" or "no surgery" and then further randomized to receive intraperitoneal injections of 1 mL phosphate-buffered saline (PBS) or 1 microgram/kg IL-10 in 1 mL PBS. Vehicle-only doses were given immediately after surgery and then every 24 hours for a total of four injections. Interleukin 10 injections were similarly given but with an added preoperative injection 30 minutes before surgery in one half of the animals. MAIN OUTCOME MEASURE: Adhesion formation. RESULTS: Animals treated with vehicle or IL-10 but not undergoing surgical intervention had no intraperitoneal adhesions. Animals undergoing surgery who were treated with IL-10, with or without a preoperative dose, had significantly lower postoperative adhesion scores than did control animals who postoperatively received PBS only. CONCLUSION: Interleukin-10 is effective at limiting postoperative intraperitoneal adhesion formation with minimal evident systemic side effects.

Elevated interleukin-6 levels in peritoneal fluid of patients with pelvic pathology.

OBJECTIVE: To determine if interleukin 6 (IL-6) is a normal constituent of peritoneal fluid (PF), and if various types of pelvic pathology influence its presence within the PF microenvironment. STUDY DESIGN: Peritoneal fluid from 73 women obtained at the time of laparoscopy was examined for the presence of IL-6 using an IL-6 specific sandwich enzyme-linked immunosorbent assay. Thirty-nine patients had pelvic endometriosis, 17 had nonendometriotic pelvic adhesive disease, and 17 subjects undergoing tubal sterilization without evidence of pelvic pathology served as controls. RESULTS: Immunoreactive IL-6 was observed in the PF of all 73 subjects (range 0.26 to 11.16 ng/mL). The mean concentration of IL-6 was higher in women with nonendometriotic pelvic adhesions as compared with control subjects (1.28 +/- 0.16 versus 0.80 +/- 0.06 ng/mL, P less than 0.03). There was no difference in the mean peritoneal concentrations of IL-6 between women with endometriosis (1.16 +/- 0.28 ng/mL) and controls, P = 0.38. Twenty-seven of 73 patients (37%) demonstrated elevated levels (greater than 1.0 ng/mL) of IL-6. Patients with pelvic adhesions were significantly more likely to have elevated concentrations of IL-6 than controls (10/17 [59%] versus 3/17 [18%], P less than 0.02). Alternatively, the percentage of patients with elevated IL-6 concentrations did not differ between patients with endometriosis or controls (14/39 [36%] versus 3/17 [18%], P greater than 0.10). CONCLUSIONS: These findings demonstrate that IL-6 is a normal constituent of PF and that elevated levels are found in many patients with pelvic adhesions.

Interleukin 6 and cancer treatment.

Interleukin 6 (IL-6) is a pleiotropic cytokine, with a wide range of biological effects. The diverse biological actions of IL-6 could play important roles in the enhancement or suppression of tumor growth and development. IL-6 has been seen to act as an autocrine and/or paracrine growth factor for various human tumors, including multiple myeloma, renal cancer, and AIDS-associated Kaposi's sarcoma. However, IL-6 also can exert potent anti-tumor effects: administration of IL-6 has been seen to result in decreased tumor appearance in experimental animal systems. Therefore, potentially useful anti-tumor therapeutic strategies could include the inhibition of the activity of IL-6, or alternatively, the enhancement of anti-tumor responses by the administration of exogenous IL-6.

Molecular and biologic factors in the pathogenesis of ovarian cancer.

The development and progression of epithelial ovarian cancer can be correlated with various biologic and molecular factors. Tumor growth has been associated with aberrant and dysfunctional expression and mutation of various genes. These genetic defects include oncogene overexpression, amplification or mutation, aberrant tumor suppressor gene expression or mutation, and the inappropriate expression of cytokines and growth factors and/or the cellular receptors for these molecules. Dysregulation of host immune responses may also play a permissive role in the pathogenesis of the disease. Since ovarian cancer has been associated with the frequency of ovulation, the repeated proliferation of epithelial cells may increase the chance of a genetic accident that could contribute to the activation of an oncogene or inactivation of a suppressor gene. These events, combined with the inherent ability of ovarian epithelial cells to respond to and produce various cytokines and growth factors, could promote oncogenesis.

Natural killer cell-mediated cytotoxicity in cryptococcal meningitis.

There are evidences regarding the role of NK cytotoxic activity in the resistance against experimental C. neoformans infection. To assess the status of NK cell activity in human C. neoformans infection, we studied the peripheral blood of twelve patients with cryptococcal meningitis, six patients with CNS disease different to cryptococcal meningitis, and twelve healthy subjects. The number of CD16+cells and the NK cytotoxic activity of peripheral blood mononuclear cells was studied. The in vitro effect of exogenous IL-2 and interferon gamma on such cytotoxic activity was also studied. The number of CD16+ cells was not significantly different in patients compared to controls. However, cryptococcal patients exhibited a significant lower NK activity compared to both control groups (p less than 0.05 in both cases). The low NK activity of cryptococcal patients was fully reconstituted in vitro with the addition of rIL-2 but not with rIFN gamma. In vitro experiments suggest that the low NK activity of cryptococcal meningitis patients is not due to amphotericin B therapy or blockade of NK cells by C. neoformans-derived molecules. The results of this study suggests that patients with cryptococcal meningitis have a defective NK cytotoxic function and may aid to understand the pathogenesis of this disease.

Enhanced cytotoxicity of an anti-transferrin receptor IgG3-avidin fusion protein in combination with gambogic acid against human malignant hematopoietic cells: functional relevance of iron, the receptor, and reactive oxygen species.

The human transferrin receptor (hTfR) is a target for cancer immunotherapy due to its overexpression on the surface of cancer cells. We previously developed an antibody-avidin fusion protein that targets hTfR (anti-hTfR IgG3-Av) and exhibits intrinsic cytotoxicity against certain malignant cells. Gambogic acid (GA), a drug that also binds hTfR, induces cytotoxicity in several malignant cell lines. We now report that anti-hTfR IgG3-Av and GA induce cytotoxicity in a new broader panel of hematopoietic malignant cell lines. Our results show that the effect of anti-hTfR IgG3-Av is iron-dependent whereas that of GA is iron-independent in all cells tested. In addition, we observed that GA exerts a TfR-independent cytotoxicity. We also found that GA increases the generation of reactive oxygen species that may play a role in the cytotoxicity induced by this drug. Additive cytotoxicity was observed by simultaneous combination treatment with these drugs and synergy by using anti-hTfR IgG3-Av as a chemosensitizing agent. In addition, we found a concentration of GA that is toxic to malignant hematopoietic cells but not to human hematopoietic progenitor cells. Our results suggest that these two compounds may be effective, alone or in combination, for the treatment of human hematopoietic malignancies.

The effect of atopy, childhood crowding, and other immune-related factors on non-Hodgkin lymphoma risk.

OBJECTIVE: Since adult immune responsiveness is influenced by early childhood exposures, we examined the role of family size, history of atopic disease, and other childhood immune-related exposures in a multi-center case-control study of NHL. METHODS: Interviews were completed with 1,321 cases ascertained from population-based cancer registries in Seattle, Detroit, Los Angeles and Iowa, and with 1,057 frequency-matched controls, selected by random-digit dialing and from the Medicare files database. Multivariable logistic regression was used to estimate risk. RESULTS: A history of any allergy (excluding drug allergies), decreased risk of all NHL (Odds Ratio [OR] = 0.7, 95% Confidence Interval [CI] = 0.6-1.0), diffuse large B-cell lymphoma [DLBCL] (OR = 0.6, 95% CI = 0.4-0.9), and follicular NHL (OR = 0.7, 95 CI = 0.5, 1.0). A similar effect was observed for hay fever. A history of eczema was associated with an increased risk of follicular lymphoma (OR = 1.9, 95% CI = 1.1-3.4), but not DLBCL (OR = 1.1, 95% CI = 0.6-2.0). Asthma did not affect risk. Youngest compared to oldest siblings had a 90% increased risk of DLBCL (95% CI = 1.2-3.1; p for trend with increasing birth order = 0.006), but not follicular lymphoma (OR = 1.1, 95% CI = 0.6-1.8). CONCLUSIONS: We infer that some childhood and immune-related factors may alter NHL risk.