Vincent Hurez | University of Texas Health Science Center at San Antonio (UTHSCSA) (original) (raw)

Papers by Vincent Hurez

Cancer research, Jan 1, 2012

Although cancer tends to affect the elderly, most preclinical studies are performed in young subj... more Although cancer tends to affect the elderly, most preclinical studies are performed in young subjects. In this study, we developed a melanoma-specific cancer immunotherapy that shows efficacy in aged but not young hosts by mitigating age-specific tumor-associated immune dysfunction. Both young and aged CD4 + CD25 hi regulatory T cells (Tregs) exhibited equivalent in vitro T cell suppression and tumor-associated augmentation in numbers. However denileukin diftitox (DT)-mediated Treg depletion improved tumor-specific immunity and was clinically effective only in young mice. DT-mediated Treg depletion significantly increased myeloid-derived suppressor cell (MDSC) numbers in aged but not young mice, and MDSC depletion improved tumor-specific immunity and reduced tumor growth in aged mice. Combining Treg depletion with anti-Gr-1 antibody was immunologically and clinically more efficacious than anti-Gr-1 antibody alone in aged B16-bearing mice, similar to Treg depletion alone in young mice. In contrast, DT increased MDSC in young and aged mice following MC-38 tumor challenge, although effects were greater in aged mice. Anti-Gr1 boosted DT effects in young but not aged mice. Aged antitumor immune effector cells are therefore competent to combat tumor when underlying tumorassociated immune dysfunction is appropriately mitigated, but this dysfunction varies with tumor, thus also varying responses to immunotherapy. By tailoring immunotherapy to account for agerelated tumor-associated immune dysfunctions, cancer immunotherapy for aged patients with specific tumors can be remarkably improved.

Aging …, Jan 1, 2012

Regulatory T cells (Tregs) are specialized CD4(+) T lymphocytes helping defend against autoimmuni... more Regulatory T cells (Tregs) are specialized CD4(+) T lymphocytes helping defend against autoimmunity and inflammation. Although age is associated with increased inflammation and autoimmunity, few reports address age effects of immune regulation or auto-aggressive T cells. We show here that young and aged naïve CD4(+) T cells are equivalently auto-aggressive in vivo in T cell-driven autoimmune colitis. Young and aged CD4(+) Tregs equally suppressed age-matched T cell proliferation in vitro and controlled clinical and pathologic T cell-driven autoimmune colitis, suggesting equivalent regulatory function. However, whereas young and aged CD4(+) Tregs suppressed interferon (IFN)-γ(+) T cells equivalently in this model, aged CD4(+) Tregs unexpectedly failed to restrain interleukin (IL)-17(+) T cells. Nonetheless, young and aged CD4(+) Tregs equally restrained IL-17(+) T cells in vivo during acute inflammation, suggesting a chronic inflammation-related defect in aged CD4(+) Tregs. In support, aged Tregs expressed reduced STAT3 activation, a defect associated with poor IL-17-producing T cell restraint. Aged naïve mice had markedly increased programmed death (PD)-1(+) T cells, but these exhibited no significant auto-aggressive or regulatory functions in T cell-driven colitis. Young CD8(+) CD122(-) T cells induce autoimmune bone marrow failure, but we show that aged CD8(+) CD122(-) T cells do not. These data demonstrate no apparent age-related increase in auto-aggressive T cell behavior, but disclose previously unrecognized functional defects in aged CD4(+) Tregs during chronic inflammation. IL-17 can be inflammatory and contributes to certain autoimmune disorders. Reduced aged Treg function during chronic inflammation and reduced IL-17 restraint could contribute to age-related inflammation or autoimmunity.

Aging cell, Jan 1, 2012

Because most patients with cancer are aged and because immunological functions are altered during... more Because most patients with cancer are aged and because immunological functions are altered during aging, it is important to account for aging-associated immunological alterations in the design of new cancer immunotherapies. We thus compared immune populations in young and aged mice and found that B7-DC + (PD-L2 ⁄ CD273) B cells, a minor population in young mice, were significantly increased in aged mice. Induction of both Th1 and Th17 cells was significantly augmented by B7-DC + B cells from aged mice, and this effect was blocked with anti-B7-DC antibodies in vitro and in vivo. Moreover, retardation of tumor growth in aged mice was largely B7-DC dependent. Tumor growth in young mice was significantly inhibited by immunization with B7-DC + B cells from aged mice owing to increased induction of tumor antigen-specific cytotoxic T lymphocytes. These data indicate that B7-DC + B cells could play an important role in aging-associated cancer immunopathology as well as in other aging-associated diseases and further suggest that B7-DC + B cells have potential for future cancer immunotherapy.

The Journal of …, Jan 1, 2010

CD4 + CD25 + Foxp3 + regulatory T cells (Tregs) are immunopathogenic in cancers by impeding tumor... more CD4 + CD25 + Foxp3 + regulatory T cells (Tregs) are immunopathogenic in cancers by impeding tumor-specific immunity. B7homologue 1 (B7-H1) (CD274) is a cosignaling molecule with pleiotropic effects, including hindering antitumor immunity. In this study, we demonstrate sex-dependent, B7-H1-dependent differences in tumor immunity and response to immunotherapy in a hormone-independent cancer, murine B16 melanoma. Antitumor immunity was better in B7-H1 2/2 females versus males as a result of reduced regulatory T cell function in the B7-H1 2/2 females, and clinical response following B7-H1 blockade as tumor immunotherapy was significantly better in wild-type females than in males, owing to greater B7-H1 blockade-mediated reduction of Treg function in females. Wild-type female Tregs expressed significantly lower B7-H1 versus males but were insensitive to estrogen in vitro. Female B7-H1 2/2 Tregs were exquisitely sensitive to estrogen-mediated functional reduction in vitro, suggesting that B7-H1 effects occur before terminal Treg differentiation. Immune differences were independent of known B7-H1 ligands. Sex-dependent immune differences are seldom considered in designing immune therapy or interpreting immunotherapy treatment results. Our data demonstrate that sex is an important variable in tumor immunopathogenesis and immunotherapy responses through differential Treg function and B7-H1 signaling.

Nature Chemical …, Jan 1, 2010

Bruton's tyrosine kinase (BTK) plays a critical role in the development, differentiation and prol... more Bruton's tyrosine kinase (BTK) plays a critical role in the development, differentiation and proliferation of B-lineage cells, making it an attractive target for the treatment of rheumatoid arthritis. The objective of this study was to evaluate the antiarthritis effect of GDC-0834 (R-N-(3-(6-(4-(1,4-dimethyl-3-oxopiperazin-2yl)phenylamino)-4-methyl-5-oxo-4,5-dihydropyrazin-2-yl)-2-methylphenyl)-4,5,6,7tetrahydrobenzo[b]thiophene-2-carboxamide), a potent and selective BTK inhibitor, and characterize the relationship between inhibition of BTK phosphorylation (pBTK) and efficacy. GDC-0834 inhibited BTK with an in vitro IC 50 of 5.9 nM and 6.4 nM in biochemical and cellular assays, respectively, and in vivo IC 50 of 1.1 and 5.6 μ M in mouse and rat, respectively. Administration of GDC-0834 (30 to 100 mg/kg) in a rat collagen-induced arthritis (CIA) model resulted in dose-dependent decrease of ankle swelling and reduction of morphologic pathology. An integrated disease progression pharmacokinetic/pharmacodynamic model where efficacy is driven by pBTK inhibition was fit to ankle diameter time course data. This model incorporated a transit model to characterize non-drug related decreases in ankle swelling occurring at later stages of disease progression in CIA rats. The time-course of ankle swelling in vehicle animals was described well by the base model. Simultaneous fitting of data from vehicle and GDC-0834 treated groups showed that overall 73% inhibition of pBTK was needed to decrease the rate constant describing the ankle swelling increase (k in ) by half. These findings suggest a high degree of pBTK inhibition is required for maximal activity of the pathway on inflammatory arthritis in rats. Downloaded from arthritis progression in the rat. Pharm Res 26: 196-203. Earp JC, Dubois DC, Molano DS, Pyszczynski NA, Almon RR, and Jusko WJ (2008b) Modeling corticosteroid effects in a rat model of rheumatoid arthritis II: mechanistic pharmacodynamic model for dexamethasone effects in Lewis rats with collagen-induced arthritis. J Pharmacol Exp Ther 326: 546-554.

Revue Francaise D Allergologie Et D Immunologie Clinique, Jan 1, 1994

Les IgG polyvalentes humaines à usage intraveineux (Ig IV) sont obtenues à partir d'un pool de pl... more Les IgG polyvalentes humaines à usage intraveineux (Ig IV) sont obtenues à partir d'un pool de plasmas de sujets sains. Utilisées initialement comme traitement substitutif chez les sujets déficients en immunoglobulines, les Ig IV se sont révélées efficaces dans le traitement du purpura thrombopénique idiopathique (PTI) 6 and 18, puis dans le traitement d'un nombre croissant de pathologies auto-immunes, de maladies inflammatories et au cours des allogreffes [14]. Nous aborderons les mécanismes à l'origine des propriétés immunomodulatrices des Ig IV.

Proceedings of the …, Jan 1, 1999

A diverse pattern of polymorphism is defined for the paired Ig-like receptors (PIRs) that serve a... more A diverse pattern of polymorphism is defined for the paired Ig-like receptors (PIRs) that serve as activating (PIR-A) and inhibitory (PIR-B) receptors on B lymphocytes, dendritic cells, and myeloid-lineage cells in mice. The monoclonal anti-PIR antibody 10.4 is shown to recognize an allelic PIR-A͞PIR-B determinant on cells from BALB͞c but not C57BL͞6 mice. Other strains of inbred mice also can be typed on the basis of their expression of this PIR allelic determinant. Analysis of (BALB͞c ؋ C57BL͞6) F 1 hybrid offspring indicates that PIR molecules bearing the paternal PIR allotype are expressed whereas PIR-A and PIR-B molecules bearing the maternal allotype are not. The monoallelic expression of the polymorphic PIR-A and PIR-B molecules, and possibly of their human Ig-like transcript͞leukocyte Ig-like receptor͞ monocyte/macrophage Ig-like receptor and killer cell inhibitory receptor relatives, may inf luence innate and specific immune responses in outbred populations.

Journal of …, Jan 1, 1993

Multiple …, Jan 1, 1997

Significant progress has been made in understanding the mechanisms by which intravenous immunoglo... more Significant progress has been made in understanding the mechanisms by which intravenous immunoglobulins (IVIg) exert immunomodulatory effects in the treatment of autoimmune diseases. A unique property of immunoglobulins is the diversity of variable (V) regions. The evidence discussed in this communication supports our notion that the diversity of V regions in IVIg preparations is a determining factor for the anti-inflammatory substitutive and immunomodulatory functions of IVIg therapy. We have demonstrated the presence in IVIg, of anti-idiotypic antibodies directed against various autoantibodies. The ability of IVIg to interact through V regions with complementary V regions of antibodies and antigen receptors as well as with relevant soluble and surface molecules provides the basis for inducing the selection of immune repertoires. The study of the mechanisms by which IVIg mediates selection of autoreactive repertoires is essential for our understanding of the mechanisms underlying the emergence of pathological autoimmunity and of the physiological role of natural antibodies in the establishment and maintenance of tolerance to self and homeostasis of autoreactivity in healthy individuals.

Immunologic …, Jan 1, 2002

Technologies for transfer of exogenous genes into primary T cells have been limited until recentl... more Technologies for transfer of exogenous genes into primary T cells have been limited until recently. The introduction of new approaches for gene transfer viadifferent viral vectors has expan ded the options for genetic manipulation of primary T cells and has provided powerful tools for studies of T cell activation and differentiation. We provide a brief overview of the systems currently available and contranst the advantages and disadvantages of each. We also describe a new transgenic model that enables highly efficient gene delivery into primary T cells by nonreplic ating adenoviral vectors.

The Journal of Immunology, Jan 1, 2003

BMC …, Jan 1, 2002

Background: Gene transfer studies in primary T cells have suffered from the limitations of conven... more Background: Gene transfer studies in primary T cells have suffered from the limitations of conventional viral transduction or transfection techniques. Replication-defective adenoviral vectors are an attractive alternative for gene delivery. However, naive lymphocytes are not readily susceptible to infection with adenoviruses due to insufficient expression of the coxsackie/ adenovirus receptor.

Molecular and cellular …, Jan 1, 2003

European journal of …, Jan 1, 1993

In the present study we have analyzed the changes in the expressed antibody repertoire and in tem... more In the present study we have analyzed the changes in the expressed antibody repertoire and in temporal fluctuations of antibody levels in serum that followed infusion of normal IgG (IVIg) in a patient with autoimmune thyroiditis. Administration of IVIg resulted in the stimulation of IgM production, in alterations of expressed antibody activity in serum that could not merely be accounted for by the passive transfer of antibody specificities contained in IVIg, in transient down-regulation of B cells clones expressing a specific disease-related idiotype and in the increase in serum in recipient's autoantibodies specifically reactive with F(ab′)2 fragments of IVIg. In addition, infusion of IVIg shifted the pattern of spontaneous fluctuations of autoantibody activities in the patient's serum from a pattern indicative of disconnected events in the immune network to a pattern similar to that which is consistently observed in healthy controls. These results suggest that normal IgG may modulate autoreactivity by selecting expressed antibody repertoire through V region-dependent interactions with antibodies.

Journal of autoimmunity, Jan 1, 1993

Infusion of intravenous immunoglobulin (IVIg) has resulted in clinical improvement and/or a fall ... more Infusion of intravenous immunoglobulin (IVIg) has resulted in clinical improvement and/or a fall in autoantibody in a number of autoimmune and inflammatory diseases. Several lines of evidence demonstrate that IVIg may react with disease-associated autoantibodies through idiotypic interactions. In addition, infusion of IVIg results in changes in the expressed autoantibody repertoire that are dependent on interactions between variable regions of infused IgG and autoantibodies and in the subsequent alterations in the regulatory function of immune networks. Thus, pooled normal immunoglobulin restored in a patient with autoimmune thyroiditis the dynamics of spontaneous fluctuations of serum autoantibodies characteristic of physiological conditions. The ability of IVIg to interact with V regions of autoantibodies and with surface molecules of lymphocytes in vitro provides a basis for the selective modulation of B-cell clones observed in patients treated with immunoglobulins. The natural intrinsic complexity of IVIg provides a physiological rationale for immunoregulatory therapy of autoimmune disease.

Immunology Letters, Jan 1, 1997

Normal human serum contains IgM antibodies that regulate the natural autoantibody activity of IgG... more Normal human serum contains IgM antibodies that regulate the natural autoantibody activity of IgG in autologous serum. In the present study, we show that pooled normal human IgM (IVIgM) purified from plasma of more than 2,500 healthy donors and processed in a similar fashion to that of therapeutic preparations of pooled normal human IgG (IVIg) suppresses activity of IgG autoantibodies purified from the serum of patients with autoimmune diseases in vitro. The inhibitory effect of IVIgM was greater or equivalent to that of IVIg on a molar basis. We show that IVIgM contains anti-idiotypic antibodies directed against idiotypic determinants of autoantibodies, in particular by showing that Sepharose-bound IVIgM selectively retained F(ab&amp;#39;)2 fragments of IgG autoantibodies. The infusion of (Lewis x Brown-Norway) F1 rats with IVIgM protected the animals against experimental autoimmune uveitis induced by immunization with the soluble retinal S antigen, as evidenced by clinical scoring and histopathological analysis. The present findings provide a rationale for considering pooled IgM for immunomodulation of autoimmune disease.

Scandinavian Journal of Immunology, Jan 1, 1993

Polyreactivity was earlier recognized as a feature of naturally expressed autoantibodies in serum... more Polyreactivity was earlier recognized as a feature of naturally expressed autoantibodies in serum. In the present study, we have compared the reactivity on a panel of self antigens of affinity-purified anti-DNA and anti-thyroglobulin (TG) IgG autoantibodies from the serum of patients with systemic lupus erythematosus (SLE) and autoimmune thyroiditis with their affinity-purified counterparts isolated from the serum of healthy individuals. Anti-DNA autoantibodies exhibited a similar degree of polyreactivity whether originating from patients or from healthy adults. Natural anti-TG autoantibodies were also found to be polyreactive. Anti-TG autoantibodies from patients with Hashimoto's thyroiditis showed little or no polyreactivity. Natural anti-TG autoantibodies were equally polyreactive whether or not they belonged to a fraction of normal IgG that is connected through V regions with other IgG molecules from the same source. These results indicate that polyreactivity of autoantibodies is a feature that does not allow one to distinguish between natural and disease-associated autoantibodies as well as between V-region-connected and unconnected autoantibodies.

The Journal of …, Jan 1, 2003

Vox Sanguinis, Jan 1, 1993

Leukocyte-depleted platelet concentrates were prepared from pools of 4 buffy coats on the day aft... more Leukocyte-depleted platelet concentrates were prepared from pools of 4 buffy coats on the day after blood collection (BC-PC). The storage medium was composed of citrate phosphate dextrose plasma and a platelet-additive solution. Autologous transfusions of 111In-labelled platelets in 9 healthy volunteers were performed on the day of preparation (day 1) and on day 5. The recovery was 54.6±8.7 (day 1) and 51.9±10.4% (day 5), T1/2 was 101±28 and 61±9 h, respectively. The survival was 8.3±1.7 and 5.7±1.0 days, respectively, using linear plot, and 7.8±2.0 and 5.8±0.5 days using the multiple hit method. In a prospective clinical study a comparison of the corrected posttransfusion increments was made between BC-PCs and apheresis-PCs, and between fresh (1–2 days) and stored (3–5 days) preparations. No difference was found between BC-PCs and apheresis PCs. However, fresh BC-PCs gave higher increments than stored BC-PCs. A slight numerical difference between fresh and stored apheresis-PCs was not statistically significant. It is concluded that the BC-PC method results in platelets of equal quality to apheresis-PC.