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stimulation with LPS in the absence of Toll-like receptor 4 (TLR4).6 However, in additional experiments, the study demonstrates that C3a activation in macrophages and dendritic cells results in phosphorylation of the ERK-1/2 and that efflux of ATP is dependent on phosphorylation of ERK-1/2 but which is independent of pannexin-1. What is missing? Complement activation is unquestionably one of the first steps in sterile inflammation. Although demonstrating that the role of C3a is a welcomed contribution to understanding the inflammatory component of acute rejection, why use LPS as the activator of the monocyte/macrophage or the dendritic cell when there is no LPS involved in rejection? Whereas deletion of TLR4 in mice reduces disease severity, all TLRs share with IL-1 receptors is the intracellular Toll–IL-1 receptor domain, which activates MyD88 for the TLRs as well as the IL-1 receptor. The Asgari study would have had a greater and broader relevance if the authors had used IL-1a as the stimulant for IL-1b production rather than LPS,7 as the precursor of IL-1a is released readily at the same time of complement activation, is active as a precursor, and causes sterile inflammation in the absence of TLR signaling. 8,9 Moreover, there is no dearth of the IL-1a precursor in renal epithelial cells. In fact, the relevant “cocktail” for induction of IL-17 would be anti-CD3/CD28 in the presence of IL-1a and engagement of C3aR. The evidence that “autoinflammation” means IL-1 induction of IL-1 can be found in the downregulation of caspase-1 in monocytes of patients treated with anakinra.10 Anakinra, which blocks both IL-1a and IL-1b, would be the clinical lesson from the Asgari study in order to reduce renal allograft rejection. Conflict-of-interest disclosure: The author declares no competing financial interests. n REFERENCES 1. Asgari E, Le Friec G, Yamamoto H, et al. C3a modulates IL-1b secretion in human monocytes by regulating ATP efflux and subsequent NLRP3 inflammasome activation. Blood. 2013;122(20): 3473-3481. 2. Dinarello CA, Simon A, van der Meer JW. Treating inflammation by blocking interleukin-1 in a broad spectrum of diseases. Nat Rev Drug Discov. 2012;11(8):633-652. 3. Kastner DL, Aksentijevich I, Goldbach-Mansky R. Autoinflammatory disease reloaded: a clinical perspective. Cell. 2010;140(6):784-790.

4. Ben-Sasson SZ, Hu-Li J, Quiel J, et al. IL-1 acts directly on CD4 T cells to enhance their antigen-driven expansion and differentiation. Proc Natl Acad Sci USA. 2009;106(17):7119-7124.

interleukin 1 in rabbits in vivo and in human mononuclear cells in vitro. J Immunol. 1987;139(6):1902-1910. 8. Chen CJ, Kono H, Golenbock D, Reed G, Akira S, Rock KL. Identification of a key pathway required for the sterile inflammatory response triggered by dying cells. Nat Med. 2007;13(7):851-856.

5. Netea MG, Nold-Petry CA, Nold MF, et al. Differential requirement for the activation of the inflammasome for processing and release of IL-1beta in monocytes and macrophages. Blood. 2009;113(10): 2324-2335.

9. Rider P, Carmi Y, Guttman O, et al. IL-1a and IL1b recruit different myeloid cells and promote different stages of sterile inflammation. J Immunol. 2011;187(9): 4835-4843.

6. Kanneganti TD, Lamkanfi M, Kim YG, et al. Pannexin-1-mediated recognition of bacterial molecules activates the cryopyrin inflammasome independent of Toll-like receptor signaling. Immunity. 2007;26(4): 433-443.

10. Goldbach-Mansky R, Dailey NJ, Canna SW, et al. Neonatal-onset multisystem inflammatory disease responsive to interleukin-1beta inhibition. N Engl J Med. 2006;355(6):581-592.

7. Dinarello CA, Ikejima T, Warner SJ, et al. Interleukin 1 induces interleukin 1. I. Induction of circulating

© 2013 by The American Society of Hematology

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Comment on Monnereau et al, page 3492

Shedding light on UVR and Hodgkin lymphoma ----------------------------------------------------------------------------------------------------Lindsay M. Morton1 and D. Michal Freedman1

1

NATIONAL INSTITUTES OF HEALTH

In this issue of Blood, Monnereau and colleagues pool 4 retrospective (case-control), observational epidemiologic studies to demonstrate an inverse association between UV radiation (UVR) exposure and risk of developing Hodgkin lymphoma (HL).1

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n recent years there has been considerable interest in the investigation of UVR and lymphoid malignancies. Most of the research has focused on non-HL, with initially conflicting data ultimately yielding to generally consistent inverse associations, although the biological mechanism underlying the relation is unclear. Fewer investigations have considered a potential association between UVR and HL, likely due in part to the relative rarity of the disease. However, in this issue of Blood, Monnereau et al1 advance the field by pooling data from 4 casecontrol studies of HL conducted in Europe, reporting that UVR is associated with reduced risk of HL, particularly Epstein-Barr virus (EBV)-positive HL (pooled odds ratio 5 0.56, 95% confidence interval 0.35-0.91 for the highest vs lowest UVR exposure). Pooling data across epidemiologic studies has key strengths and weaknesses that merit discussion. The main advantage lies in the large sample size, particularly for investigation of disease or patient subgroups. Additionally, pooled studies use individual-level data,

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which, unlike meta-analyses, allow exposure variables in each study to be redefined to a common scale. On the other hand, as Monnereau et al acknowledge,1 these harmonized variables may in fact obscure variability in exposure definitions arising from differences in the wording and structure of study questionnaires. More importantly, the detailed exposure characterization that may make an individual study so valuable is unlikely to be similar across studies, so the range of exposure variables that can be considered in a pooled analysis is often limited. Monnereau et al leveraged the strengths of a pooled analysis to provide the first investigation of personal history of UVR exposure and HL according to disease subtype, taking into account HL histology as well as tumor EBV status.1 Interestingly, the data suggest that the inverse association may be stronger for EBV-positive than EBV-negative tumors. Although the finding requires confirmation, evidence for etiologic heterogeneity within HL has accumulated

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Global mean erythemal UVR daily dose (J/m2) during 2011-2012, based on data from the Ozone Monitoring Instrument on the National Aeronautics and Space Administration’s Aura satellite as cited in Levelt et al.6 In addition to personal behaviors such as the amount of time spent outside and use of sun-protective clothing, ambient UVR is an important consideration in estimating UVR exposure histories because of its substantial variation by geographical location. Figure created by Dr Douglas C. Morton (NASA’s Goddard Space Flight Center, Greenbelt).

since the idea was first proposed nearly half a century ago2 and should be a priority for future investigation. The measurement of UVR exposure is particularly complex, and the current report was somewhat hindered by the data available in the individual studies. The primary exposure metric was overall relative UVR exposure, calculated for each individual based on self-reported data in various formats, including time outdoors on working and nonworking days (2 studies), time outdoors doing routine leisure activities (2 studies), or frequency of sunbathing in the summertime (1 study). All 4 studies also had at least some data on sunlamp use. Three main issues with the exposure assessment indicate that more research is needed to evaluate the potential association between UVR and HL. First, as a retrospective study, Monnereau et al relied on recollections made after HL diagnosis regarding time spent outdoors,1 which may

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have been distorted by the status of being ill. Although prospective studies would be small, they could provide useful confirmatory evidence. Second, Monnereau et al combined occupational and recreational exposures into a single metric,1 but 2 of the studies that contributed data to this pooled analysis reported a null or nonsignificantly positive association for occupational UVR and HL.3,4 Inconsistency in the findings between occupational and recreational exposures may harbor a clue to the disease association, because occupational exposures are frequently chronic, whereas recreational exposures are intermittent. Alternatively, the inconsistency may suggest a role for recall bias in reporting recreational exposures, because occupational exposures are likely to be more accurately reported. Finally, Monnereau et al1 did not take ambient UVR into account. Although personal behaviors contribute considerably to the variability in UVR exposure,5 the substantial variability in UVR by location (see

figure6) modifies the impact of these behaviors. Indeed, ambient exposure has been used as an informative metric for UVR exposure in epidemiologic studies, with 2 recent such studies reporting conflicting results for HL.7,8 If the association between UVR and HL is causal, then the biological mechanism by which UVR contributes to lymphomagenesis is unclear. Previous research has focused on a potential role for vitamin D, which is generated by cutaneous sun exposure, has receptors expressed on most lymphocytes, and has been shown in vitro to impact the immune system in various ways.1,7 Despite excitement about this hypothesis, a large pooled analysis of 10 cohort studies showed no association for circulating 25-hydroxyvitamin D with non-HL,9 and the only study to examine circulating 25-hydroxyvitamin D and HL also was null,10 though these studies were limited by the use of a single measure of vitamin D. Alternative pathways, such as UVR induction of

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regulatory T cells, also are plausible but require further investigation. Few modifiable risk factors for HL have been identified, and the scientific evidence is insufficient to conclude that either UVR or vitamin D is related to HL risk. However, the results of this pooled study should catalyze further research into UVR and HL. In addition to molecular studies, further epidemiologic research that can address key methodologic issues such as consideration of HL subtypes, recall bias, and integration of personal behaviors, occupational exposures, and ambient UVR has the greatest potential for shedding light on the etiology of HL. Conflict-of-interest disclosure: The authors declare no competing financial interests. n

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Comment on Deckert et al, page 3500

In the spotlight: a novel CD37 antibody-drug conjugate ----------------------------------------------------------------------------------------------------M. Lia Palomba1 and Anas Younes1

1

MEMORIAL SLOAN-KETTERING CANCER CENTER

In this issue of Blood, Deckert et al make a strong argument in favor of IMGN529, a novel anti-CD37 maytansinoid antibody-drug conjugate (ADC), elegantly showing its activity against B-cell lymphoma in in vitro and in vivo preclinical studies.1

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alone in patients with chronic lymphocytic leukemia (CLL) experiencing relapse. An Fc-engineered anti-CD37 monoclonal antibody, in which the Fc portion of the antibody is altered to enhance affinity for Fc-gRIIIa, is also in early development.5 Finally, another CD37-directed therapeutic currently under investigation in humans is betalutin, a 177Lu-labeled anti-CD37 antibody.6 Ultimately, the superiority of one of these compounds over the others will strictly depend on its ability to exert potent antitumor activity by engaging multiple pathways of cytotoxicity. ADCs are complex engineered molecules composed of an antibody linked via a stable linker to a potent cytotoxic drug or payload, which preferentially kill tumor cells while sparing toxic effects on healthy tissues. Once the ADC binds to its cell surface target, it is internalized, releasing the toxic payload inside the cell. In general, the payload of ADCs is either a DNA binder (calicheamicin) or a tubulin binder. There are 2 major classes of tubulin binders: maytensins and auristatins. Within the maytensins, DM1 and DM4 are currently being used, with different potency and toxicity profiles. The brentuximab vedotin payload is an aurostatin derivative,7 whereas the trastuzumab emtansine payload is a DM1 maytensin.8 Other conjugates are also being explored, including chemotherapy agents (see table). The strong efficacy of the poster children of ADCs, brentuximab vedotin and trastuzumab emtansine, resulted in their being approved by the US Food and Drug Administration (FDA) for relapsed Hodgkin lymphoma and anaplastic large-cell lymphoma, and for metastatic breast cancer, respectively. Other ADCs currently being

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REFERENCES 1. Monnereau A, Glaser SL, Schupp C, et al. Exposure to ultraviolet radiation and risk of Hodgkin lymphoma: a pooled analysis. Blood. 2013;122(20):3492-3499. 2. Jarrett RF. Viruses and Hodgkin’s lymphoma. Ann Oncol. 2002;13(Suppl 1):23-29. 3. Smedby KE, Hjalgrim H, Melbye M, et al. Ultraviolet radiation exposure and risk of malignant lymphomas. J Natl Cancer Inst. 2005;97(3):199-209. 4. Boffetta P, van der Hel O, Kricker A, et al. Exposure to ultraviolet radiation and risk of malignant lymphoma and multiple myeloma—a multicentre European case-control study. Int J Epidemiol. 2008;37(5):1080-1094. 5. Dadvand P, Basagaña X, Barrera-G´omez J, Diffey B, Nieuwenhuijsen M. Measurement errors in the assessment of exposure to solar ultraviolet radiation and its impact on risk estimates in epidemiological studies. Photochem Photobiol Sci. 2011;10(7):1161-1168. 6. Levelt PF, van den Oord GHJ, Dobber MR, et al. The Ozone Monitoring Instrument. IEEE Trans Geosci Rem Sens. 2006;44:1093-1101. 7. Chang ET, Canchola AJ, Cockburn M, et al. Adulthood residential ultraviolet radiation, sun sensitivity, dietary vitamin D, and risk of lymphoid malignancies in the California Teachers Study. Blood. 2011;118(6):1591-1599. 8. van Leeuwen MT, Turner JJ, Falster MO, et al. Latitude gradients for lymphoid neoplasm subtypes in Australia support an association with ultraviolet radiation exposure. Int J Cancer. 2013;133(4):944-951. 9. Lim U, Freedman DM, Hollis BW, et al. A prospective investigation of serum 25-hydroxyvitamin D and risk of lymphoid cancers. Int J Cancer. 2009;124(4):979-986. 10. Purdue MP, Freedman DM, Gapstur SM, et al. Circulating 25-hydroxyvitamin D and risk of non-hodgkin lymphoma: Cohort Consortium Vitamin D Pooling Project of Rarer Cancers. Am J Epidemiol. 2010;172(1):58-69.

D37 is a member of the transmembrane 4 superfamily of tetraspanin proteins, which consist of 4 potential membranespanning regions, 2 extracellular loops and 2 short intracytoplasmic tails.2 Although most tetraspanins are ubiquitous proteins, CD37 expression is nearly exclusively limited to mature B cells and B-cell–derived lymphoid malignancies. B-cell early progenitors, T cells, natural killer cells, and myeloid cells exhibit only minimal amounts of membraneassociated CD37. This relative lineage restriction makes CD37 a suitable target for immunotherapy. In the late 1980s, a 131I-labeled anti-CD37 monoclonal antibody was developed for human use, resulting in significant responses in patients with B-cell non-Hodgkin lymphoma (NHL).3 Further developments were hampered by the success of rituximab and other anti-CD20–directed therapies, and CD37 was put on the back burner for several years. However, one of the most remarkable innovations in targeting the CD37 antigen emerged a few years ago with the development of a CD37-specific small modular immunopharmaceutical,4 an engineered protein that includes anti-CD37 variable regions linked to an immunoglobulinconstant domain. The CD37-specific small modular immunopharmaceutical demonstrated robust antitumor activity against lymphoid malignancies in preclinical studies, including in human lymphoma xenograft models. Its humanized counterpart, TRU-016 (otlertuzumab), has similar activity in preclinical models, was shown to have synergistic activity in combination with other agents, and is currently being evaluated in a randomized study in combination with bendamustine compared with bendamustine

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2013 122: 3395-3397 doi:10.1182/blood-2013-09-527648

Shedding light on UVR and Hodgkin lymphoma Lindsay M. Morton and D. Michal Freedman

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Shedding light on UVR and Hodgkin lymphoma.

In this issue of Blood, Monnereau and colleagues pool 4 retrospective (case-control), observational epidemiologic studies to demonstrate an inverse as...
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