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PubMed1993

A human monoclonal antibody, produced following in vitro immunization, recognizing an epitope shared by HLA-A2 subtypes and HLA-A28.

In vitro immunization and subsequent immortalization of peripheral blood cells of a multiparous woman has resulted in the production of a stable human mouse heterohybridoma, 5C2A2, secreting an HLA-A2/A28-specific human monoclonal antibody. Although possibly exposed to HLA-A2 by transfusions, the cell donor showed no HLA-A2-specific serum antibodies. The present protocol for in vitro immunization includes the elimination of suppressor cells from the responder cell population, the presence of irradiated allogeneic lymphocytes as a source of antigen, as well as stimuli--recombinant interleukin-2 and a B-cell specific nucleoside analogue--causing the proliferation of B lymphocytes, prior to immortalization. The ability of the antibody 5C2A2 to detect all known HLA-A2 subtypes, except A2.3, and A28, allows identification of the serological epitope on the HLA-A2 molecule. Application of this in vitro immunization method allows the production of a set of HLA monoclonal antibody-secreting human hybridomas, independent of the existence of serum HLA antibodies in the lymphocyte donors.

Amino Acid Sequence↗
PubMed2002

Mouse and human dendritic cell subtypes.

Dendritic cells (DCs) collect and process antigens for presentation to T cells, but there are many variations on this basic theme. DCs differ in the regulatory signals they transmit, directing T cells to different types of immune response or to tolerance. Although many DC subtypes arise from separate developmental pathways, their development and function are modulated by exogenous factors. Therefore, we must study the dynamics of the DC network in response to microbial invasion. Despite the difficulty of comparing the DC systems of humans and mice, recent work has revealed much common ground.

Animals↗
PubMed1999

Altered expression and action of the low-affinity IgE receptor FcepsilonRII (CD23) in asthmatic airway smooth muscle.

BACKGROUND: Changes in cell surface expression of certain immunoglobulin Fc receptors have been demonstrated in leukocytes isolated from the lungs of atopic asthmatic individuals. This, together with emerging evidence that Fc receptors can also be expressed and activated in non-bone marrow-derived cell types, including airway smooth muscle (ASM), raises the hypothesis that the atopic asthmatic ASM phenotype is associated with an altered endogenous expression and action of specific Fc receptors present in the ASM itself. OBJECTIVE: The current study addressed the above hypothesis by examining (1) whether the expression of certain key Fc receptor subtypes for IgE and IgG is altered in ASM tissue isolated from human atopic asthmatic individuals and (2) whether this altered Fc receptor expression is comparably induced in naive human ASM tissue and cultured cells after their passive sensitization with human atopic asthmatic serum or IgE immune complexes. METHODS: Messenger RNA and cell surface protein expression of the individual IgG receptor subtypes FcgammaRI, FcgammaRII, and FcgammaRIII, as well as the IgE receptor subtypes FcepsilonRI and FcepsilonRII, were examined in human ASM tissue isolated from atopic asthmatic and control (nonatopic/nonasthmatic) individuals. In addition, we examined the effects of passive sensitization of ASM tissue and cultured ASM cells with control serum, atopic asthmatic serum, or exogenously administered IgE immune complexes on Fc receptor expression and action (ie, induction of proinflammatory cytokine release). RESULTS: The observations demonstrate that (1) human ASM tissue expresses messenger RNA and surface protein for FcepsilonRII, as well as for all the Fcgamma receptor subtypes, (2) in contrast to unaltered Fcgamma subtype expression, however, relative to control human ASM, FcepsilonRII is significantly up-regulated in inherently asthmatic ASM tissue, (3) up-regulated expression of FcepsilonRII represents, at least in part, an inducible phenomenon that is largely attributed to IgE immune complex-coupled activation of the receptor, and (4) the latter action is associated with FcepsilonRII-induced autologous elaboration of the proinflammatory cytokine, IL-1beta, by the atopic sensitized ASM. CONCLUSION: These observations provide new evidence that human ASM tissue expresses FcepsilonRII in addition to all 3 subtypes of Fcgamma receptors and that the expression of FcepsilonRII is selectively increased in atopic asthmatic ASM, a phenomenon associated with IgE immune complex/FcepsilonRII-mediated elaboration of IL-1beta by the ASM itself.

Adolescent↗
PubMed2006

Ancestral and consensus envelope immunogens for HIV-1 subtype C.

Immunogens based on "centralized" (ancestral or consensus) HIV-1 sequences minimize the genetic distance between vaccine strains and contemporary viruses and should thus elicit immune responses that recognize a broader spectrum of viral variants. However, the biologic, antigenic and immunogenic properties of such inferred gene products have to be validated experimentally. Here, we report the construction and characterization of the first full-length ancestral (AncC) and consensus (ConC) env genes of HIV-1 (group M) subtype C. The codon-usage-optimized genes expressed high levels of envelope glycoproteins that were incorporated into HIV-1 virions, mediated infection via the CCR5 co-receptor and retained neutralizing epitopes as recognized by plasma from patients with chronic HIV-1 subtype C infection. Guinea pigs immunized with AncC and ConC env DNA developed high titer binding, but no appreciable homologous or heterologous neutralizing antibodies. When tested by immunoblot analysis, sera from AncC and ConC env immunized guinea pigs recognized a greater number of primary subtype C envelope glycoproteins than sera from guinea pigs immunized with a contemporary subtype C env control. Mice immunized with AncC and ConC env DNA developed gamma interferon T cell responses that recognized overlapping peptides from the cognate ConC and a heterologous subtype C Env control. Thus, both AncC and ConC env genes expressed functional envelope glycoproteins that were immunogenic in laboratory animals and elicited humoral and cellular immune responses of comparable breadth and magnitude. These results establish the utility of centralized HIV-1 subtype C Env immunogens and warrant their continued evaluation as potential components of future AIDS vaccines.

AIDS Vaccines↗
PubMed2004

Intranasal immunization with genetically detoxified diphtheria toxin induces T cell responses in humans: enhancement of Th2 responses and toxin-neutralizing antibodies by formulation with chitosan.

We previously reported that intranasal immunization with a non-toxic mutant cross-reacting material (CRM)197 of diphtheria toxin, formulated with chitosan, generated protective neutralizing antibodies in mice and guinea pigs. Furthermore, we demonstrated that intranasal delivery of a powder formulation of the CRM197-based vaccine was well tolerated and significantly boosted antibody responses in adult volunteers. Here we report that intranasal booster immunization with CRM197 alone or with chitosan induced systemic T cell responses. We addressed for the first time the induction of T cell subtypes following intranasal vaccination in humans. Intranasal vaccination with CRM197, like parenteral immunization with a conventional diphtheria toxoid vaccine, enhanced antigen-specific IFN-gamma production. However, formulation of the nasal diphtheria vaccine with chitosan significantly augmented Th2-type responses, which correlated with protective levels of toxin-neutralizing antibodies in intranasally boosted individuals. The results suggest that vaccines capable of inducing strong Th2-type responses, such as CRM197 formulated with chitosan, have potential for the development of a protective mucosal vaccine against diphtheria in humans. Furthermore, our findings demonstrate that mucosal subunit vaccines with appropriate delivery systems have considerable potential for booster immunization of adults.

Administration, Intranasal↗
PubMed1999

Inhibition of MT-450 rat mammary tumour growth by antibodies recognising subtypes of blood group antigen B.

Using subtractive immunization to identify cell surface epitopes expressed in a metastasis-specific fashion on cells of the rat MT-W9 mammary carcinoma model, we generated a monoclonal antibody called M-N#1. This antibody binds specifically to metastasizing cells of the MT-W9 series and also to certain other metastasizing rat mammary carcinoma cell lines. We demonstrate that the M-N#1 antibody recognizes a fucosylated N-glycosyl sugar modification, and furthermore show that the epitope specificity of the M-N#1 antibody is for blood group antigen B subtypes 2, 3 and 4 with slight cross-reactivity with blood group antigen A subtype 2. The expression of these carbohydrate epitopes on MT-450 cells is functionally important, because the M-N#1 antibody efficiently inhibits MT-450 tumour growth in spontaneous metastasis assays. These results suggest that expression of the subtypes of blood group antigen B recognized by the M-N#1 antibody does not directly participate in the metastatic cascade but rather confers a growth or survival advantage on the tumour cells.

ABO Blood-Group System↗
PubMed1992

[Fc gamma receptors: structure, function, and clinical significance].

Fc gamma receptors are a group of three different receptors with several subtypes. They are widely distributed on many cells of the immune system and contribute to the pathogenesis of immune complex- and autoantibody-mediated diseases such as vasculitis, rheumatoid arthritis, idiopathic thrombocytopenic purpura or autoimmune neutropenia. This review focuses on the structure, distribution and function in Fc gamma receptors and their subtypes.

Antigen-Antibody Complex↗
PubMed2026

ARHGAP22 as a Potential Prognostic Biomarker in Clear Cell Renal Cell Carcinoma: Insights into Tumor Immunity and Co-Expression Networks.

Clear cell renal cell carcinoma (ccRCC) is the most common subtype of kidney cancer and is characterized by substantial clinical heterogeneity, highlighting the need for reliable prognostic biomarkers. This study evaluated the expression pattern, prognostic relevance, and immune-related associations of ARHGAP22 in ccRCC using transcriptomic and clinical data from The Cancer Genome Atlas Kidney Renal Clear Cell Carcinoma (TCGA-KIRC) cohort, together with external validation data and protein-expression information from the Human Protein Atlas (HPA). ARHGAP22 expression was compared between tumor and adjacent normal tissues, and its associations with overall survival, clinicopathological characteristics, tumor microenvironment scores, and estimated immune-cell fractions were assessed. Co-expression and functional-enrichment analyses were also performed to characterize potential biological associations. ARHGAP22 was significantly upregulated in ccRCC tissues at the transcriptomic level, with corresponding differences observed in immunohistochemical images. High ARHGAP22 expression was associated with shorter overall survival, advanced clinicopathological features, and higher ImmuneScore, StromalScore, and ESTIMATEScore values. CIBERSORT-based analysis showed that the high-expression group had higher estimated fractions of M2 macrophages and regulatory T cells and lower estimated fractions of naïve B cells, resting mast cells, and activated dendritic cells after false discovery rate correction. Functional-enrichment analyses linked ARHGAP22-associated genes to immune-related processes, cell migration, and chemokine- and cytokine-mediated signaling pathways. These findings suggest that ARHGAP22 may represent a potential prognostic and immune-related biomarker in ccRCC, although further independent clinical and experimental validation is required.

Humans↗
PubMed1985

Murine helper T lymphocyte response to influenza virus: recognition of haemagglutinin by subtype-specific and cross-reactive T cell clones.

Helper T cel lines specific for influenza virus were established by continuous culture of Mem 71-Bel (H3) virus-immune spleen cells in the presence of virus and antigen-presenting cells and their specificity assessed in proliferation experiments. A line stimulated in vitro with Mem 71-Bel virus was able to proliferate in response to viruses of the same, and also of different, type A haemagglutinin (HA) subtypes as the immunizing virus but not to a type B influenza virus. A component of this cross-reactivity was due to recognition of the HA molecule. Lines stimulated in vitro with purified disrupted H3 or H2 viruses showed a higher degree of cross-reactivity. Of nine clones isolated from these lines, seven were directed against the HA molecule and recognized the HA1 chain. The HA-specific T cell clones were either subtype-specific T cell clones were either subtype-specific, recognizing only viruses of the H3 subtype, or cross-reactive, also recognizing viruses of the H2 subtype of type A (but not type B). Subtype-specific and cross-reactive T cell clones were shown to function as helper T cells in vitro. In addition to collaborating with H3 virus-primed B cells responding to H3 virus in culture, the cross-reactive T cell clone could also provide help for H2 virus-primed B cells making anti-HA antibody in response to H2 virus.

Animals↗
PubMed2026

Evolution and heterogeneity of lethal metastatic bladder cancer subtypes.

Histological variation is a prognostic feature of metastatic urothelial cancer1-3, but its evolutionary trajectory remains poorly defined. We developed a metastatic bladder cancer rapid autopsy programme enriched in histological subtypes4 to profile individuals with terminal disease. Here by reconstructing the evolutionary histories of patient tumours, we show that metastasis-to-metastasis seeding is the dominant pattern of cancer spread and that increased polyclonal migration predicts poor prognosis. The burden, heterogeneity and timing of genomic alterations differ markedly among histological subtypes. Plasmacytoid and neuroendocrine variants develop early driver alterations associated with shorter survival. Mutational signature analyses and experimental models demonstrated that plasmacytoid tumours uniquely use the Fanconi anaemia pathway to mitigate chemotherapy-induced genomic scarring. Single-nucleus profiling revealed mixed cell states in histological subtypes and an association between transcriptional heterogeneity and patient survival. Characterization of the tumour microenvironment uncovered distinct immune states across subtypes, with plasmacytoid tumours exhibiting immune-inflamed profiles, whereas squamous tumours are predominantly immunosuppressive. Last, we demonstrate that post-mortem cell-free DNA captures genomic and transcriptional heterogeneity of the subtypes, which provides a potential strategy for noninvasive assessment of tumour identity and aggressiveness. Our results provide new insights into how tumour heterogeneity shapes the evolutionary history of disease progression in bladder cancer histological subtypes.

Journal Article↗
PubMed2002

The modulatory effects of prostaglandin-E on cytokine production by human peripheral blood mononuclear cells are independent of the prostaglandin subtype.

The production of inflammatory mediators, relevant to (auto)immune diseases and chronic inflammatory conditions, can be modulated by dietary intake of n-3 and n-6 long chain polyunsaturated fatty acids (PUFAs). It was suggested that these effects are related to the formation of different series of eicosanoids, in particular prostaglandin-E (PGE). In this study we investigated whether prostaglandin subtypes metabolized from arachidonic acid (PGE2), dihomo-gamma-linolenic acid (PGE1) or eicosapentaenoic acid (PGE3) have different effects on T-cell proliferation and cytokine production in vitro. Freshly isolated human peripheral blood mononuclear cells (PBMC) were stimulated with concanavalin A (ConA) or lipopolysaccharide (LPS) in the presence or absence of exogenous PGE1, PGE2 or PGE3. We found that tumour necrosis factor-alpha (TNF-alpha), interferon-gamma (IFN-gamma) and to a lesser extent interleukin (IL)-10 production was inhibited by all PGE-subtypes in ConA-stimulated PBMC concomitant with unaffected IL-2 levels. The modulated cytokine production of ConA stimulated cells was independent of T-cell proliferation. PGE2 and PGE1 moderately stimulated proliferation, while PGE3 inhibited the proliferative response to some extent. In LPS-stimulated PBMC, TNF-alpha production was inhibited by all PGE-subtypes, whereas IL-6 remained unaffected and IL-10 production was increased. Time course experiments on the effects of PGE-subtypes on cytokine production after ConA or LPS stimulation showed these effects to be time dependent, but indifferent of the prostaglandin subtype added. Overall, the modulatory effects of PGE on cytokine production were irrespective of the subtype. This may implicate that the immunomodulatory effects of PUFAs, with respect to cytokine production, are not caused by a shift in the subtype of PGE.

Alprostadil↗
PubMed2003

Immunotherapy for lymphomas.

A growing list of immunotherapeutic strategies is now being employed to combat lymphoid malignancies. These efforts are warranted given that B-cell lymphomas, particularly those of the common follicular subtype, are among the most "immune-responsive" of all human cancers. Although systemic cytokine therapies for B-cell malignancies have been largely disappointing to date, monoclonal antibody therapies, principally the anti-CD20 antibody rituximab, have already made enormous impact on the treatment algorithm for many B-cell lymphomas. Therapeutic vaccines targeting the tumor-specific immunoglobulin idiotype have demonstrated promising results against lymphomas in phase I/II studies and are currently being evaluated in phase III randomized trials. Additional vaccine therapies being developed include those based on dendritic cells, recombinant idiotype proteins, DNA, heat shock proteins, and gene-modified tumor cells. It is hoped that immunotherapeutic agents, used in tandem or in combination, may someday allow effective treatment of lymphoid malignancies and delay or even replace the need for conventional cytotoxic therapies.

Antibodies, Monoclonal↗
PubMed1984

Frequency of lambda light chain subtypes in mouse antibodies to the 2,4-dinitrophenyl (DNP) group.

Of the three lambda chain subtypes made by inbred mice, chains of the lambda 1 subtype are much more frequent than those of the other subtypes (lambda 2,lambda 3) in antibodies (Ab) to those few antigenic structures that are known to elicit responses, in which lambda chains are the predominant type of light chain [(4-hydroxy-3-nitrophenyl)acetyl (NP) and dextran]. The reason for the frequency differences are not understood, and the large difference between the lambda 1 and lambda 3 frequencies is particularly puzzling, because in nearly all (about 95%) chains of these subtypes the N-terminal 97 or 98 amino acids are endoded by the same V lambda-gene segment. In an effort to identify an Ab response that has different lambda subtype frequencies, we analyzed the light chains of the Ab made by BALB/c and B6 mice in response to 2,4-dinitrophenylated chicken gamma globulin (DNP-CGG). We found that approximately 40% of the elicited anti-DNP molecules had lambda chains and of these approximately 40% were of the lambda 2 or lambda 3 subtype. Polyacrylamide gel electrophoresis indicated that the lambda 2 and lambda 3 chains were about equally abundant. Similar lambda subtype frequencies were found in the anti-DNP Ab produced by the hybridoma made with spleen cells from the same immunized mice. In the anti-DNP Ab elicited by DNP-CGG and in the anti-NP Ab elicited by NP-CGG the different lambda subtype frequencies (lambda 1/lambda 2 + lambda 3 = ca. 1.0-1.5 in anti-DNP and ca. 30 in anti-NP) were unaffected by immunizing mice with each of these antigens alone or with a mixture of the two. This finding, though preliminary, suggests that isotype-specific regulatory T cells are not responsible for the markedly different lambda subtype frequencies in anti-DNP and anti-NP Ab.

2,4-Dinitrophenol↗
PubMed2002

Differential intracellular expression of CCR5 and chemokines in multiple sclerosis subtypes.

Chemokines are small chemoattractant cytokines which participate in the migration of immune cells into the CNS and contribute to the T cell-mediated pathogenesis of multiple sclerosis (MS). The expression of chemokines and their receptors in freshly isolated mononuclear cells from peripheral blood (PBMC) was studied in relation to MS subtype, disease duration and progression in a total of 57 patients with MS (22 relapsing remitting, RRMS; 21 secondary progressive, SPMS; 14 primary progressive, PPMS) and 17 healthy controls. The RNA expression of CCR5 in PBMC was analysed by reverse transcription polymerase chain reaction (RT-PCR) using specific oligonucleotide primers. The PBMC levels of CCR5-ligands MIP-1 alpha/beta and RANTES, and chemokines MCP-1, IL-8, lymphotactin, IP-10 and I-309 were analysed by ribonuclease protection assay (RPA). Significantly increased intracellular CCR5 RNA expression intensity was detected in PPMS when compared with SPMS ( p=0.009), RRMS ( p=0.013), and controls ( p=0.023). However, the surface expression of CCR5 on CD4(+) cells from PBMC, analysed by flow cytometry, appeared to be similar in all MS subtypes and controls. The CCR5-ligands RANTES and MIP-1b were expressed constitutively in all patients and controls. Interleukin-8 was found in all MS subtypes and controls, but IP-10 was detected only in RRMS and SPMS, and lymphotactin occasionally in other subtypes but PPMS. MCP-1, MIP-1a or I-309 were not expressed in any of the groups studied. A correlation was found between the RNA levels of RANTES and CCR5 in PPMS ( r=0.735). Differential profile in the expression of CCR5 and chemokines between PPMS and other MS subtypes may contribute to differences in the pathogenesis of MS and thus can be of importance in the development of new treatments for MS.

Adult↗
PubMed2005

[In vitro stimulation of specific antileukemia T-cell response by dendritic cells derived from CD14+ acute monocytic leukemia cells].

BACKGROUND & OBJECTIVE: Dendritic cells (DCs) or DC-like cells had been successfully induced in vitro from leukemia cells, which may provide a promising immunotherapeutic protocol for leukemia. This study was designed to investigate the efficiency of in vitro generation of dendritic cells from CD14+ acute myelomonocytic (M4) or monocytic (M5) leukemia cells and their ability of stimulating specific antileukemia T-cell response. METHODS: Bone marrow mononuclear cells (BMMNCs) were isolated from 5 M4/M5 leukemia patients with high CD14 expression, and then divided into 3 groups: adherent leukemia cells, nonadherent blasts, and total unfractioned blasts. CD14 expression of the 3 groups was evaluated by flow cytometry (FCM). When cultured with or without granulocyte-macrophage colony-stimulating factor (GM-CSF), interleukin-4 (IL-4) and tumor necrosis factor alpha (TNF-alpha) for 7-10 days, monocytic leukemia cell-derived dendritic cells (Mo-LDCs) were identified through morphologic observation and immunophenotype analysis using FCM. The immune function of Mo-LDCs was detected through allogeneic mixed lymphocyte reaction (Allo-MLR) and cytotoxicity assay of antileukemia cytotoxic T lymphocytes (CTLs). The leukemic origin of Mo-LDCs was confirmed by chromosomal karyotype analysis combined with the aberrant expression of myeloid antigens. RESULTS: The amount of CD14+ cells, which could differentiate into CD83+ mature DCs under induction of the cytokine combination, was higher in adherent leukemia cells than in nonadherent blasts and total unfractioned blasts. Regarding each 3 cell groups of the same patient or the unfractioned blasts of various patients, initial CD14 expression was positively related to the yield of CD83+ DCs after induction (r = 0.967, P = 0.007). Mo-LDCs exhibited typical morphology and phenotype as mature DCs, induced potent proliferation of homogeneous T cells in Allo-MLR, stimulated the expansion of leukemia-specific CTLs, and continued to possess the cytogenetic abnormalities of the original leukemia, as well as the aberrant expression of myeloid antigens. CONCLUSIONS: In M4/M5 subtype of AML, CD14+ cells could differentiate into immune-competent Mo-LDCs under the induction of the cytokine combination. CD14 expression level may predict the DCs differentiation ability of monocytic leukemia. Mo-LDCs, which possess the classical phenotype and function of DCs, as well as the abnormal leukemic antigens, may be useful for the immunotherapy of M4/M5 AML.

Adolescent↗
PubMed2004

Exposure to low doses of solar-simulated radiation induces an increase in the myeloid subtype of blood dendritic cells.

Exposure to ultraviolet radiation causes alterations of cutaneous and systemic immunity. The aim of our study was to assess the influence of low doses of solar-simulated radiation (SSR) on the phenotypes of blood dendritic cells (BDC). Healthy volunteers (94) were irradiated with a dose of 1.2 SED (standard erythema dose) of SSR for 2, 10 or 30 consecutive days. Blood samples were taken before the first exposure and 24 h after final exposure. The three main subsets of BDC were distinguished by flow cytometry: BDCA-2(+)/CD123(+)/HLA-DR(+) (plasmacytoid, PDC) and two myeloid subtypes BDCA-1(+)/CD11c(+)/HLA-DR(+) (MDC1) and BDCA-3(+)/CD32(-)/HLA-DR(+) (MDC2). The percentage of total DC was elevated in all groups by the UV exposure and was significantly increased after 2 and 30 days of irradiation (P = 0.006 and P = 0.018, respectively). A particularly distinct increase was observed in the percentage of the MDC1 after 2 and 30 days (P = 0.022 and P < 0.0001, respectively). The MDC2 showed an increase after 10 days and a subsequent significant decrease after 30 days of irradiation (P = 0.031). A significant increase in PDC was found after 2 days of irradiation (P = 0.0006). Exposure to SSR induced an increase in the percentage of BDC in healthy human individuals, especially apparent in the MDC1 subtype.

Adult↗
PubMed1998

Efficacy evaluation of prime-boost protocol: canarypoxvirus-based feline immunodeficiency virus (FIV) vaccine and inactivated FIV-infected cell vaccine against heterologous FIV challenge in cats.

OBJECTIVE: To evaluate the immunogenicity and prophylactic efficacy of immunization schemes employing a recombinant canarypoxvirus ('ALVAC')-based feline immunodeficiency virus (FIV) vaccine alone or in combination with an inactivated FIV-infected cell vaccine against homologous and heterologous FIV challenges in cats. METHODS: Specific pathogen-free cats were given a total of three immunizations with subtype A vaccines and challenged 4 weeks after the final immunization with 50 median animal infectious doses (ID50) of FIV-Petaluma, a subtype A isolate. Following the initial challenge, protected cats received a second challenge with 75 ID50 of FIV-Bangston, a subtype B isolate. FIV-specific humoral and cell-mediated responses were measured to determine the immune correlates of protection. RESULTS: Two of three cats immunized with the ALVAC FIV recombinants alone were protected from homologous FIV challenge in the presence of FIV-specific cytotoxic T-lymphocyte (CTL) responses but in the absence of FIV-specific humoral responses. All three cats immunized with the ALVAC-FIV recombinant and boosted with FIV-infected cell vaccine were also protected from homologous FIV challenge in the presence of both FIV-specific CTL and humoral responses. Partial to full protection was observed in ALVAC-FIV/FIV-infected cell vaccine-immunized cats against a heterologous FIV challenge given 8 months after the initial challenge. Two out of three cats had transient infection and the remaining cat had no sign of FIV infection at a dose at which all three control cats were readily infected. CONCLUSIONS: Immunization schemes employing ALVAC-based FIV vaccines in combination with inactivated FIV-infected cell vaccine generate protective immune responses that can cross-react with FIV isolates that are genetically distinct from the vaccine strains.

Animals↗
PubMed2026

Myeloid-Mediated Immunoregulation and Resistance to Immune Checkpoint Inhibitor Therapy Across Squamous Cell Carcinomas: Mechanisms and Reprogramming Strategies.

Immune checkpoint inhibitors (ICIs) targeting PD-1/PD-L1 have improved outcomes across squamous cell carcinomas (SCCs) of the head and neck, lung, esophagus, and skin, yet durable responses remain confined to a subset of patients in every subtype. Objective response rates vary substantially across SCCs despite overlapping genomic alterations, comparable tumor mutational burden, and high PD-L1 expression, indicating that tumor-intrinsic biomarkers alone do not explain this variability. Growing evidence points to the tumor immune microenvironment, and in particular the myeloid compartment, as a critical determinant of immunotherapy responsiveness. In this review, we synthesize current evidence on myeloid-mediated immune regulation across SCC subtypes, focusing on tumor-associated macrophages, myeloid-derived suppressor cells/tumor-associated neutrophils, and dendritic cells, and the mechanisms by which these populations impair antigen presentation, restrict T cell infiltration, and sustain immunologically "cold" tumor states. We further examine therapeutic strategies aimed at reprogramming rather than simply depleting suppressive myeloid populations, including radiation therapy, STING agonism, and myeloid-targeted agents (CSF1R, PI3K&#x3b3;, and CXCR2 inhibition), each of which has shown encouraging preclinical and early clinical activity in combination with ICI. Collectively, this evidence supports a model in which the myeloid compartment functions as an actionable, convergent determinant of ICI resistance across SCC subtypes, rather than merely a passive biomarker. We propose that through the integration of spatial and single-cell profiling of myeloid states with clinical history it will be possible to predict response to immune checkpoint therapy and personalize myeloid-directed combination strategies, though the specific biomarkers needed to match individual patients to a given myeloid-targeted approach remain to be defined. We further discuss the toxicity considerations associated with both immune checkpoint blockade and radiation-based combination approaches, the early-phase status of most myeloid-targeted agents currently in clinical development, and the extent to which mechanistic insight, derived predominantly from HNSCC, generalizes to squamous cell carcinomas arising at other anatomic sites.

dendritic cells↗