AUTOIMMUNE RETINOPATHY MIMICKING HERITABLE RETINAL DEGENERATION IN A PATIENT WITH COMMON VARIABLE IMMUNE DEFICIENCY.

PURPOSE: 1) To describe a case of autoimmune retinopathy mimicking heritable photoreceptor degeneration in a patient with common variable immune deficiency and 2) to investigate the humoral and cell-mediated branches of the immune system in this patient to better understand the mechanism of immune-mediated photoreceptor damage in this disease. METHODS: Retrospective chart review with evaluation of multimodal imaging, genotype analysis, and investigation of circulating autoantibodies and T-cell response to retinal antigens. RESULTS: A 40-year-old woman with bilateral, progressive vision loss was referred for evaluation of a possible inherited retinal degeneration. She was found to have asymmetric peripheral visual field constriction, cystoid macular edema, vitreous cells, and bone spicule-like pigmentary changes in both eyes. An extensive workup for underlying infectious or inflammatory causes was unrevealing, and molecular analysis for heritable retinal degeneration failed to identify a plausible disease-causing genotype. Screening for antiretinal antibodies showed the presence of multiple antiretinal antibodies, consistent with a diagnosis of autoimmune retinopathy. Immunologic workup demonstrated markedly decreased levels of serum IgA and IgG, consistent with common variable immune deficiency. T-cells isolated from the patient showed increased proliferation when stimulated with human retinal proteins, supporting a role for both cell- and humoral-mediated autoimmunity. Treatment with mycophenolate mofetil and intravenous immunoglobin therapy slowed the progression of disease and resulted in preservation of her central vision. CONCLUSION: Autoimmune retinopathy can be seen in common variable immune deficiency and has clinical findings similar to heritable photoreceptor degeneration. Both the humoral and cellular immune responses are involved in the pathophysiology. Immune modulatory therapy has stabilized the disease course in this patient and may play an important role in the management of autoimmune retinopathy.

Targeted Alpha-Particle Radiotherapy and Immune Checkpoint Inhibitors Induces Cooperative Inhibition on Tumor Growth of Malignant Melanoma.

Radiotherapy can facilitate the immune recognition of immunologically "cold" tumors and enhance the efficacy of anti-PD-1 and anti-CTLA-4 immune checkpoint inhibitors (ICIs) in melanoma. Systemic administration of receptor-targeted radionuclide therapy has the potential to selectively deliver radionuclides to multiple tumors throughout the body in metastatic settings. By triggering immunologic cell death and increasing the immune susceptibility of surviving tumor cells in these locations, targeted radionuclide therapies may overcome resistance to ICIs and render immunologically "cold" tumors throughout the body responsive to ICIs and immunologically "hot". Here, we show the anti-tumor cooperation of targeted α-particle radionuclide therapy (α-TRT) and ICIs in preclinical models of melanoma. Melanocortin 1 receptor (MC1R)-targeted radiopeptide [212Pb]VMT01 was employed to deliver α-radiation to melanoma tumors in mice. A single injection of 4.1 MBq [212Pb]VMT01 significantly slowed the tumor growth of B16-F10 melanoma and the combination of [212Pb]VMT01 and ICIs induced a cooperative anti-tumor effect leading to 43% complete tumor response with no sign of malignancy on autopsy. Animals with complete response developed anti-tumor immunity to reject further tumor inoculations. This therapeutic cooperation was completely abolished in RAG1 KO mice, which are deficient in T-cell maturation. In addition, the anti-tumor cooperation was compromised when fractionated [212Pb]VMT01 was used in the combination. We also demonstrated that [212Pb]VMT01 induced immunogenic cell death in tumor vaccination assays and in vitro exposure to [212Pb]VMT01 sensitized immunotolerant melanoma to ICIs treatment in vivo. Enhanced tumor infiltrating CD3+, CD4+, CD8+ lymphocytes were observed following injection of 1.4 MBq [212Pb]VMT01. Overall, we demonstrated anti-tumor cooperation between α-TRT and ICIs in melanoma that is mediated by tumor specific immunity.

A 31-Year-Old Man With Angina Pectoris Resulting From Large Vessel Vasculitis.

We present the case of an apparently healthy 31-year-old man with malignant progression of coronary artery disease and recurrent angina resulting from suspected large vessel vasculitis. This case highlights the importance of considering vasculitis in patients without atherosclerotic risk factors, using a multidisciplinary team approach, and suppressing inflammation before coronary revascularization to improve outcomes. (Level of Difficulty: Beginner.).

Cancer in primary immunodeficiency diseases: Cancer incidence in the United States Immune Deficiency Network Registry.

BACKGROUND: We evaluated the overall and site-specific incidence of cancer in subjects with primary immunodeficiency diseases (PIDD) enrolled in the United States Immune Deficiency Network (USIDNET) registry compared with age-adjusted cancer incidence in the Surveillance, Epidemiology and End Results Program (SEER) database. OBJECTIVE: We hypothesized that subjects with PIDD would have an increased incidence of cancer due to impaired immune function. METHODS: Overall and site-specific cancer incidence rates were evaluated in subjects with PIDD (n = 3658) enrolled in the USIDNET registry from 2003 to 2015 and compared with age-adjusted incidence rates in the SEER database. RESULTS: We observed a 1.42-fold excess relative risk of cancer in subjects with PIDD compared with the age-adjusted SEER population (P < .001). Men with PIDD had a 1.91-fold excess relative risk of cancer compared with the age-adjusted male population (P < .001), while women with PIDD had similar overall cancer rates compared with the age-adjusted female population. Of the 4 most common malignancies in men and women in SEER (lung, colon, breast, and prostate cancers), we found no significant increase in these diagnoses in subjects with PIDD. Significant increases in lymphoma in both men (10-fold increase, P < .001) and women (8.34-fold increase, P < .001) with PIDD were observed. CONCLUSIONS: Excess incidence of cancer occurred in subjects with PIDD. An excess of lymphoma in specific PIDD populations principally drove this increased incidence, while no increased risk of the most common solid tumor malignancies was observed. These data point to a restricted role of the immune system in protecting from specific cancers.

A Personalized Diagnostic and Treatment Approach for Macrophage Activation Syndrome and Secondary Hemophagocytic Lymphohistiocytosis in Adults.

OBJECTIVE: We assessed the clinical features and outcomes based on therapeutic options adopted during hospital stay for adult patients with macrophage activation syndrome and secondary hemophagocytic lymphohistiocytosis (MAS/sHLH). METHODS: We conducted a retrospective chart review of all adult patients (age ≥ 18 years) diagnosed with MAS/sHLH at our center between 2010 and 2015. Inclusion criteria for patients were diagnosis of MAS/sHLH during admission and patients meeting at least 5 out of 8 of Henter's criteria or at least 4 out of 6 of the criteria that were tested. RESULTS: Nineteen adult patients with MAS/sHLH met the inclusion criteria from January 2010 to October 2015 (median age 48 years; female 68.4%). Treatment had been personalized, depending on the clinical presentation and course of disease. Majority of the patients received anakinra, cyclosporine, intravenous immunoglobulins (IVIG), and steroids. Fourteen (74%) patients survived, with clinical improvement by the time of discharge. After excluding the three patients with underlying leukemia/lymphoma who opted for palliative care and subsequently died, the survival rate was 88%. CONCLUSION: A modified diagnostic and treatment protocol for adult patients with MAS/sHLH that incorporated graded introduction of medications based on clinical presentation and cytokine profile resulted in the best adult survival rate reported in literature.

Nicotine Mediates CD161a+ Renal Macrophage Infiltration and Premature Hypertension in the Spontaneously Hypertensive Rat.

RATIONALE: Renal inflammation contributes to the pathophysiology of hypertension. CD161a+ immune cells are dominant in the (SHR) spontaneously hypertensive rat and expand in response to nicotinic cholinergic activation. OBJECTIVE: We aimed to phenotype CD161a+ immune cells in prehypertensive SHR after cholinergic activation with nicotine and determine if these cells are involved in renal inflammation and the development of hypertension. METHODS AND RESULTS: Studies used young SHR and WKY (Wistar-Kyoto) rats. Splenocytes and bone marrow cells were exposed to nicotine ex vivo, and nicotine was infused in vivo. Blood pressures, kidney, serum, and urine were obtained. Flow cytometry, Luminex/ELISA, immunohistochemistry, confocal microscopy, and Western blot were used. Nicotinic cholinergic activation induced proliferation of CD161a+/CD68+ macrophages in SHR-derived splenocytes, their renal infiltration, and premature hypertension in SHR. These changes were associated with increased renal expression of MCP-1 (monocyte chemoattractant protein-1) and VLA-4 (very-late antigen-4). LLT1 (lectin-like transcript 1), the ligand for CD161a, was overexpressed in SHR kidney, whereas vascular cellular and intracellular adhesion molecules were similar to those in WKY. Inflammatory cytokines were elevated in SHR kidney and urine after nicotine infusion. Nicotine-mediated renal macrophage infiltration/inflammation was enhanced in denervated kidneys, not explained by angiotensin II levels or expression of angiotensin type-1/2 receptors. Moreover, expression of the anti-inflammatory α7-nAChR (α7-nicotinic acetylcholine receptor) was similar in young SHR and WKY rats. CONCLUSIONS: A novel, inherited nicotinic cholinergic inflammatory effect exists in young SHR, measured by expansion of CD161a+/CD68+ macrophages. This leads to renal inflammation and premature hypertension, which may be partially explained by increased renal expression of LLT-1, MCP-1, and VLA-4.

Novel role for endogenous hepatocyte growth factor in the pathogenesis of intracranial aneurysms.

Inflammation plays a key role in formation and rupture of intracranial aneurysms. Because hepatocyte growth factor (HGF) protects against vascular inflammation, we sought to assess the role of endogenous HGF in the pathogenesis of intracranial aneurysms. Circulating HGF concentrations in blood samples drawn from the lumen of human intracranial aneurysms or femoral arteries were compared in 16 patients. Tissue from superficial temporal arteries and ruptured or unruptured intracranial aneurysms collected from patients undergoing clipping (n=10) were immunostained with antibodies to HGF and its receptor c-Met. Intracranial aneurysms were induced in mice treated with PF-04217903 (a c-Met antagonist) or vehicle. Expression of inflammatory molecules was also measured in cultured human endothelial, smooth muscle cells and monocytes treated with lipopolysaccharides in presence or absence of HGF and PF-04217903. We found that HGF concentrations were significantly higher in blood collected from human intracranial aneurysms (1076±656 pg/mL) than in femoral arteries (196±436 pg/mL; P<0.001). HGF and c-Met were detected by immunostaining in superficial temporal arteries and in both ruptured and unruptured human intracranial aneurysms. A c-Met antagonist did not alter the formation of intracranial aneurysms (P>0.05), but significantly increased the prevalence of subarachnoid hemorrhage and decreased survival in mice (P<0.05). HGF attenuated expression of vascular cell adhesion molecule-1 (P<0.05) and E-Selectin (P<0.05) in human aortic endothelial cells. In conclusion, plasma HGF concentrations are elevated in intracranial aneurysms. HGF and c-Met are expressed in superficial temporal arteries and in intracranial aneurysms. HGF signaling through c-Met may decrease inflammation in endothelial cells and protect against intracranial aneurysm rupture.

The Glycophosphatidylinositol Anchor of the MCMV Evasin, m157, Facilitates Optimal Cell Surface Expression and Ly49 Receptor Recognition.

The murine cytomegalovirus-encoded protein m157 is a cognate ligand for both inhibitory and activating receptors expressed by natural killer cells. Additionally, m157 is expressed on the surface of infected cells by a glycophosphatidylinositol (GPI) anchor. Although endogenous GPI-anchored proteins are known to be ligands for the NK cell receptor, NKG2D, the contribution of the GPI anchor for viral m157 ligand function is unknown. To determine whether the GPI anchor for m157 is dispensable for m157 function, we generated m157 variants expressed as transmembrane fusion proteins and tested cells expressing transmembrane m157 for the capacity to activate cognate Ly49 receptors. We found that the GPI anchor is required for high-level cell surface expression of m157, and that the transmembrane m157 ligand retains the capacity to activate reporter cells and NK cells expressing Ly49H, as well as Ly49I(129) reporter cells, but with reduced potency. Importantly, target cells expressing the transmembrane form of m157 were killed less efficiently and failed to mediate Ly49H receptor downregulation on fresh NK cells compared to targets expressing GPI-anchored m157. Taken together, these results show that the GPI anchor for m157 facilitates robust cell surface expression, and that NK cells are sensitive to the altered cell surface expression of this potent viral evasin.

Role of NK cell subsets in organ-specific murine melanoma metastasis.

Tumor metastasis plays a major role in the morbidity and mortality of cancer patients. Among solid tumors that undergo metastasis, there is often a predilection to metastasize to a particular organ with, for example, prostate cancer preferentially metastasizing to bones and colon cancer preferentially metastasizing to the liver. Although many factors are thought to be important in establishing permissiveness for metastasis, the reasons for organ-specific predilection of each tumor are not understood. Using a B16 murine melanoma model, we tested the hypothesis that organ-specific NK cell subsets play a critical role in organ-specific metastasis of this tumor. Melanoma cells, given intravenously, readily colonized the lungs but not the liver. NK cell depletion (either iatrogenically or by using genetically targeted mice) resulted in substantial hepatic metastasis. Analysis of NK cell subsets, defined by the differential expression of a combination of CD27 and CD11b, indicated a significant difference in the distribution of NK cell subsets in the lung and liver with the mature subset being dominant in the lung and the immature subset being dominant in the liver. Several experimental approaches, including adoptive transfer, clearly indicated that the immature hepatic NK cell subset, CD27+ CD11b-, was protective against liver metastasis; this subset mediated its protection by a perforin-dependent cytotoxic mechanism. In contrast, the more mature NK cell subsets were more efficient at reducing pulmonary tumor load. These data indicate that organ-specific immune responses may play a pivotal role in determining the permissiveness of a given organ for the establishment of a metastatic niche.

A phase I trial of immunostimulatory CpG 7909 oligodeoxynucleotide and 90 yttrium ibritumomab tiuxetan radioimmunotherapy for relapsed B-cell non-Hodgkin lymphoma.

Radioimmunotherapy (RIT) for relapsed indolent non-Hodgkin lymphoma produces overall response rates (ORR) of 80% with mostly partial remissions. Synthetic CpG oligonucleotides change the phenotype of malignant B-cells, are immunostimulatory, and can produce responses when injected intratumorally and combined with conventional radiation. In this phase I trial, we tested systemic administration of both CpG and RIT. Eligible patients had biopsy-proven previously treated CD20+ B-cell NHL and met criteria for RIT. Patients received rituximab 250 mg/m(2) days 1,8, and 15; (111) In-ibritumomab tiuxetan days 1, 8; CpG 7909 days 6, 13, 20, 27; and 0.4 mCi/kg of (90) Y-ibritumomab tiuxetan day 15. The doses of CpG 7909 tested were 0.08, 0.16, 0.32 (six patients each) and 0.48 mg/kg (12 patients) IV over 2 hr without dose limiting toxicity. The ORR was 93% (28/30) with 63% (19/30) complete remission (CR); median progression free survival of 42.7 months (95% CI 18-NR); and median duration of response (DR) of 35 months (4.6-76+). Correlative studies demonstrated a decrease in IL10 and TNFα, and an increase in IL1ß, in response to therapy. CpG 7909 at a dose of 0.48 mg/kg is safe with standard RIT and produces a high CR rate and long DR; these results warrant confirmation.

Neurohormonal modulation of the innate immune system is proinflammatory in the prehypertensive spontaneously hypertensive rat, a genetic model of essential hypertension.

RATIONALE: Inflammation and autonomic dysfunction contribute to the pathophysiology of hypertension. Cholinergic stimulation suppresses innate immune responses. Angiotensin II (Ang II) induces hypertension and is associated with proinflammatory immune responses. OBJECTIVE: Our goal was to define the innate immune response in a model of genetic hypertension and the influences of cholinergic stimulation and Ang II. METHODS AND RESULTS: Studies were conducted on 4- to 5-week-old prehypertensive spontaneously hypertensive rats (SHRs) and age-matched normotensive control, Wistar Kyoto (WKY) rats. Isolated splenocytes were preexposed to nicotine or Ang II before Toll-like receptor (TLR) activation. Culture supernatants were tested for cytokines (tumor necrosis factor-α, interleukin [IL]-10, and IL-6). TLR-mediated cytokine responses were most pronounced with TLR7/8 and TLR9 activation and similar between WKY rats and SHRs. Nicotine and Ang II enhanced this TLR-mediated IL-6 response in prehypertensive SHR splenocytes. In contrast, nicotine suppressed the TLR-mediated IL-6 response in WKY rats, whereas Ang II had no effect. In vivo, nicotine enhanced plasma levels of TLR7/8-mediated IL-6 and IL-1ß responses in prehypertensive SHRs but suppressed these responses in WKY rats. Flow cytometry revealed an increase in a CD161+ innate immune cell population, which was enhanced by nicotine in the prehypertensive SHR spleen but not in WKY. CONCLUSIONS: There is a pronounced anti-inflammatory nicotinic/cholinergic modulation of the innate immune system in WKY rats, which is reversed in prehypertensive SHRs. The results support the novel concept that neurohormonal regulation of the innate immune system plays a role in the pathogenesis of genetic hypertension and provide putative molecular targets for treatment of hypertension.

Phase I clinical trial of CpG oligonucleotide 7909 (PF-03512676) in patients with previously treated chronic lymphocytic leukemia.

CpG oligonucleotide 7909 (CpG 7909, PF-03512676), a synthetic 24mer single stranded agonist of TLR9 expressed by B cells and plasmacytoid dendritic cells, is immunomodulatory and can cause activation-induced death of chronic lymphocytic leukemia (CLL) cells. We report a phase I study of CpG 7909 in 41 patients with early relapsed CLL. A single intravenous dose of CpG 7909 was well tolerated with no clinical effects and no significant toxicity up to 1.05 mg/kg. Single dose subcutaneous CpG 7909 had a maximum tolerated dose (MTD) of 0.45 mg/kg with dose limiting toxicity of myalgia and constitutional effects. Multiple weekly subcutaneous doses at the MTD were well tolerated. CpG 7909 administration induced immunologic changes in CLL and non-malignant cells that were dose and route dependent. We conclude that multidose therapy with subcutaneous CpG 7909 (0.45 mg/kg) could be used in future phase II combination clinical trials for CLL.

High prevalence of humoral immunodeficiency patients with refractory chronic rhinosinusitis.

BACKGROUND: The purpose of this study was to investigate the prevalence and contribution of humoral immunodeficiency in refractory chronic rhinosinusitis (RCRS). This study was performed at a tertiary care academic referral center. METHODS: RCRS patients who had at least three episodes of documented sinusitis in the previous year despite antibiotic therapy, who had endoscopic sinus surgery performed at University of Iowa Health Care (UIHC), and who were evaluated by the UIHC Adult Immune Disorder Clinic were included. Exclusion criteria included allergic fungal sinusitis, human immunodeficiency virus, and other causes of secondary immunodeficiency. Sixty-seven patients fulfilled the inclusion and exclusion criteria. The results of their immunologic evaluation for atopy and humoral immune function were examined. RESULTS: The average age of these patients was 50 years (±11.6 years). Twenty-eight (42%) patients had at least one positive result on allergy skin testing. Determination of quantitative immunoglobulins showed low IgG in 9%, low IgA in 3%, and low IgM in 12% of patients. Common variable immunodeficiency was diagnosed in one case. Immunoglobulin G subclasses were tested in 31 cases and found low in 6 patients. Fifty-one patients underwent a dynamic assessment of their antibody response by examining the increase in antibody titer to an unconjugated pneumococcal polysaccharide vaccine. Sixty-seven percent of patients failed to produce more than a fourfold increase in postimmunization antibody titer for >7 of 14 serotypes being tested and were considered to have functional antibody deficiency. CONCLUSION: This retrospective review shows an unexpectedly high prevalence of humoral immune dysfunction in patients with RCRS. These findings suggest that assessment of immune function should be undertaken routinely in RCRS. Immune assessment should first include measurement of serum immunoglobulin levels; if these are normal, then functional antibody responses should be evaluated.

Assessment of natural killer (NK) and NKT cells in murine spleens and livers.

Natural killer (NK) cells part of innate immunity. NK cells have been assigned numerous functions, including the ability to serve as a bridge between innate and adaptive immunity. In evaluating NK cell function, two pathways need to be examined: their ability to kill certain tumors spontaneously and their ability to secrete cytokines, interferon-gamma (IFN-gamma), in particular. Although NK cells are distinct from T lymphocytes, a new lymphocyte subset, termed NKT cell, has been described. NKT cells express surface markers that are unique to NK cells (e.g., NK1.1) as well as markers that are unique to T cells (e.g., CD3). Most NKT cells recognize glycolipids and are thought to play an important immunoregulatory role. This chapter will detail the methodology needed for examination of NK and NKT cells in mice.

Modulation of NK cell activity by CpG oligodeoxynucleotides.

Oligodeoxynucleotides (ODN) with hypomethylated CpG motifs have been found to be potent stimulators of various aspects of innate and adaptive immunity. One of their major effects is the activation of natural killer (NK) killing activity in vitro and in vivo. There are several categories of CpG classified as type A, type B, and type C, although another category with inhibitory activity is being characterized further. CpG type A (CpG-A) is the most potent at activating NK cells. Examination of the cells and soluble mediators involved in this activation has led to an understanding of an interesting cascade of events. It appears that CpG activates dendritic cells (DC) which in turn activate NK-cells. This is not surprising since NK-cells do not seem to express TLR9, the CpG receptor. Of the various cytokines involved in NK-cell activation, it appears that type 1 interferon plays a pivotal role. Having activated NK-cells, DC themselves appear to become susceptible to lysis by the NK-cells they activated but with a delayed time kinetic. CpG ODN have been examined as monotherapeutic agents in murine tumor models. In one model, B16 melanoma, CpG ODN were very effective and NK cells were both necessary and sufficient for that effect. In another model, EL4 lymphoma, NK cells were necessary but not sufficient. Moreover, CpG were able to induce long-term survival in mice with established tumor. Studies in humans show similar results with potent activation in vitro. In a limited Phase I dose escalation study it also appeared that CpG ODN induce NK cell activation in humans in vivo.

Thymocytes, pre-B cells, and organ changes in a mouse model of chronic ethanol ingestion--absence of subset-specific glucocorticoid-induced immune cell loss.

BACKGROUND: The well-known immune deficiency of the chronic alcoholic dictates the need for a long-term rodent ethanol administration model to evaluate the baseline immunologic effects of chronic ethanol abuse, and investigate the genetic determinants of those effects. Much published work with rodents has shown clearly that acute ethanol administration and short-term ethanol-containing liquid diets both cause elevated corticosterone and can cause significant thymocyte, pre-B cell and peripheral lymphocyte losses. Such losses may mask more subtle alterations in immune homeostasis, and in any case are generally short-lived compared with the span of chronic ethanol abuse. Thus, it is important to have a model in which long-term immune alterations can be studied free of corticosteroid-induced cell losses. METHODS: We have utilized chronic 20% (w/v) ethanol in water administration to several mouse strains for prolonged periods of time and evaluated serum corticosterone, immunologic stress parameters, and other organ changes by standard methods. RESULTS: We now confirm earlier reports that chronic ethanol in water administration to mice does not produce net elevations of corticosterone, although diurnal variation is altered. Importantly, there is neither selective loss of immune cell populations known to be corticosteroid sensitive, CD4+CD8+ thymocytes and pre-B cells, nor are changes observed in the histologic appearance of the thymus. Nonetheless, there are significant chronic ethanol effects in other tissues, including reduced heart weight, mild hepatic steatosis, alterations of gut flora, increased serum peptidoglycan, and as published elsewhere, immune system abnormalities. CONCLUSIONS: This model of ethanol administration is convenient, sustainable for up to 1 year, demonstrably feasible in several mouse strains, permits good weight gains in most strains, and results in significant changes in a number of organs. The administration method also will permit modeling of long-term steady abuse punctuated by major binges, and is suitable for supplementation studies using water soluble additives. Overall, the method is useful for a wide range of studies requiring a chronic low-stress method of ethanol administration.

Oligodeoxynucleotide CpG 7909 delivered as intravenous infusion demonstrates immunologic modulation in patients with previously treated non-Hodgkin lymphoma.

Oligodeoxynucleotides containing CpG motifs (CpG ODN) can alter various immune cell subsets important in antibody therapy of malignancy. We undertook a phase I trial of CPG 7909 (also known as PF-3512676) in patients with previously treated lymphoma with the primary objective of evaluating safety across a range of doses, and secondary objectives of evaluating immunomodulatory effects and clinical effects. Twenty-three patients with previously treated non-Hodgkin lymphoma received up to 3 weekly 2-hour intravenous (IV) infusions of CPG ODN 7909 at dose levels 0.01 to 0.64 mg/kg. Evaluation of immunologic parameters and clinical endpoints occurred for 6 weeks. Infusion-related toxicity included grade 1 nausea, hypotension, and IV catheter discomfort. Serious adverse hematologic events observed more than once included anemia (2=Gr3, 2=Gr4), thrombocytopenia (4=Gr3), and neutropenia (2=Gr3), and were largely judged owing to progressive disease. Immunologic observations included: (1) The mean ratio of NK-cell concentrations compared with pretreatment at day 2 was 1.44 (95% CI=0.94-1.94) and at day 42 was 1.53 (95% CI=1.14-1.91); (2) NK activity generally increased in subjects; and (3) Antibody-dependent cellular cytotoxicity activity increased in select cohorts. No clinical responses were documented radiographically at day 42. Two subjects demonstrated late response. We conclude CpG 7909 can be safely given as a 2-hour IV infusion to patients with previously treated non-Hodgkin lymphoma at doses that have immunomodulatory effects.

Natural killer cells in human health and disease.

Natural killer (NK) cells are lymphocytes of the innate immune system that are critical in host defense and immune regulation. They are activated or inhibited through the ligation of germline-encoded receptors and are involved in mediating cytotoxicity, in producing cytokines and in providing co-stimulation to cells of the adaptive immune system. NK cells play important roles in viral infections, autoimmunity, pregnancy, cancer and bone marrow transplantation. This review highlights recent developments in the understanding of the role of human NK cells in health and disease.