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PubMed2001

Commentary: Immune escape versus tumor tolerance: how do tumors evade immune surveillance?

Despite an increasing understanding of immunological mechanisms it is still not clear how tumors evade immune-surveillance of the host and how tumors interact with the immune-system. In particular, the question whether tumors arise because of an insufficient immune response or whether tumor cells employ active strategies to escape the control of the immune system is still open. Data from a great number of in vitro studies and animal models offer arguments for both the theory of an immune escape as well as that of tumor tolerance. In this article the available results regarding the mechanisms of host-tumor-interaction are discussed with focus on these two contrary hypotheses.

Aging↗
PubMed1999

Expression of Fas ligand by human gastric adenocarcinomas: a potential mechanism of immune escape in stomach cancer.

BACKGROUND: Despite being immunogenic, gastric cancers overcome antitumour immune responses by mechanisms that have yet to be fully elucidated. Fas ligand (FasL) is a molecule that induces Fas receptor mediated apoptosis of activated immunocytes, thereby mediating normal immune downregulatory roles including immune response termination, tolerance acquisition, and immune privilege. Colon cancer cell lines have previously been shown to express FasL and kill lymphoid cells by Fas mediated apoptosis in vitro. Many diverse tumours have since been found to express FasL suggesting that a "Fas counterattack" against antitumour immune effector cells may contribute to tumour immune escape. AIM: To ascertain if human gastric tumours express FasL in vivo, as a potential mediator of immune escape in stomach cancer. SPECIMENS: Thirty paraffin wax embedded human gastric adenocarcinomas. METHODS: FasL protein was detected in gastric tumours using immunohistochemistry; FasL mRNA was detected in the tumours using in situ hybridisation. Cell death was detected in situ in tumour infiltrating lymphocytes using terminal deoxynucleotidyl transferase mediated dUTP nick end labelling (TUNEL). RESULTS: Prevalent expression of FasL was detected in all 30 resected gastric adenocarcinomas examined. In the tumours, FasL protein and mRNA were co-localised to neoplastic gastric epithelial cells, confirming expression by the tumour cells. FasL expression was independent of tumour stage, suggesting that it may be expressed throughout gastric cancer progression. TUNEL staining disclosed a high level of cell death among lymphocytes infiltrating FasL positive areas of tumour. CONCLUSIONS: Human gastric adenocarcinomas express the immune downregulatory molecule, FasL. The results suggest that FasL is a prevalent mediator of immune privilege in stomach cancer.

Adenocarcinoma↗
PubMed2003

Strategies for tumor immune escape.

The interactions between the immune system and malignant cells play an important role in tumorigenesis. Evidence that tumors are immunogenic continues to accumulate. Although they frequently express antigens in a form recognizable by the host immune system, tumors commonly "escape" the immune response. Tumors may therefore progress by evolving variants that can evade immune responses or by developing other strategies to avoid immune control. The purpose of this review is to evaluate the current status of knowledge concerning these different tumor-escape strategies.

Humans↗
PubMed2005

Human colorectal cancer cells induce T-cell death through release of proapoptotic microvesicles: role in immune escape.

BACKGROUND & AIMS: Normal and neoplastic cells release microvesicles, whose effects on the immune system still need to be elucidated. Because human colorectal cancer cells are hypothesized to escape immune recognition by expressing proapoptotic molecules, we investigated whether microvesicles bearing Fas ligand and tumor necrosis factor-related apoptosis-inducing ligand and inducing apoptosis of activated T cells are secreted by colorectal cancer cells both in vitro and in affected patients. METHODS: Fas ligand and tumor necrosis factor-related apoptosis-inducing ligand expression were analyzed in colorectal cancer cells and purified microvesicles by flow cytometry, Western blotting, and immunoelectron microscopy. Microvesicle tumor origin was assessed through simultaneous detection of lysosomal (CD63) and adenocarcinoma (carcinoembryonic antigen) markers. Proapoptotic activity of microvesicles was evaluated by annexin V/propidium iodide staining and caspase activation in T cells, including CD8+ T lymphocytes from colorectal cancer patients. RESULTS: Colorectal cancer cells showed a granular pattern of tumor necrosis factor-related apoptosis-inducing ligand and Fas ligand expression, suggesting a secretory behavior. These proapoptotic molecules were detected on isolated microvesicles, together with class I HLA, CD63, and carcinoembryonic antigen. Microvesicles induced Fas ligand-mediated and tumor necrosis factor-related apoptosis-inducing ligand-mediated apoptosis of activated CD8+ T cells generated from colorectal cancer patients. Microvesicles with comparable phenotypes and functions were found in plasma from patients with advanced disease, whereas vesicular structures expressing Fas ligand and tumor necrosis factor-related apoptosis-inducing ligand were also detected in colorectal cancer specimens. CONCLUSIONS: These data show that colorectal cancer induces T-cell apoptosis through the release of Fas ligand-bearing and tumor necrosis factor-related apoptosis-inducing ligand-bearing microvesicles both in vitro and in vivo. This mechanism of immune escape has potential implications as a prognostic factor and could be targeted for the development of new antitumor therapies in colorectal cancer patients.

Apoptosis↗
PubMed2003

[Study on blocking the tumor immune escape by Fas ligand pathway].

The expression of Fas ligand (FasL) on the membrane of many kinds of leukemia or solid tumor cells played an important role in the immune escape of tumor cells. This study was aimed to know if the soluble Fas (sFas), expressed by adenovirus, could block the immune escape of tumor cells by FasL pathway. The two recombinant adenoviral vectors, AdsFas with murine soluble Fas gene and AdEGFP with enhanced GFP protein gene, were constructed by homologous recombination between two plasmids in Escherichia coli with the AdEasy adenovirus vector system. The viruses were propagated and purified by two times ultracentrifugation. Their titres were detected by plaque assays. The expressed protein was evaluated by Western blot analysis. Then the tumor EL4 cells were infected with AdsFas and AdEGFP respectively. The apoptosis ratio of the target cells-YAC-1 cells induced by EL4 cells was respectively detected by (3)H-thymidine ((3)H-TdR) labeling. The results showed that the recombinant adenoviral vectors AdsFas and AdEGFP were successfully obtained. The titres of viruses purified by two times ultracentrifugation were up to 10(11) pfu/ml by plaque assays. The sFas protein was highly expressed in the target cells by Western blot analysis. After the EL4 cells were transfected with the adenoviruses AdsFas, the apoptosis rate of YAC-1 cells in the sFas transfection group (respectively 6%, 7% and 9% when the effector:target (E:T) was 3:1, 10:1 and 30:1) was obviously lower than that in the control group (respectively 28%, 37% and 45%), P < 0.01. But when the EL4 cells were transfected with AdEGFP, the apoptosis rate of YAC-1 cells (respectively 30%, 36% and 48%) was similar to the control group, P > 0.05. In conclusion, the transfer of sFas by adenovirus could inhibit the apoptosis of Fas(+) cells-YAC-1 cells induced by tumor EL4 cells. It showed that the transduction of sFas could block the effect of the immune escape of EL4 cells through FasL in vitro. These results thus provide a new direction to find a way to treat tumors.

Adenoviridae↗
PubMed2025

One thousand SARS-CoV-2 antibody structures reveal convergent binding and near-universal immune escape.

Understanding antibody recognition and adaptation to viral evolution is central to vaccine and therapeutic development. Over 1,100 SARS-CoV-2 antibody structures have been resolved, marking the largest structural biology effort for a single pathogen. We present a comprehensive analysis of this landmark dataset to investigate the principles of antibody recognition and immune escape. Human immunoglobulins and camelid single-chain antibodies dominate, collectively mapping 99% of the receptor-binding domain. Despite remarkable sequence and conformational diversity, antibodies exhibit convergence in their paratope structures, revealing evolutionary constraints in epitope selection. Analyses reveal near-universal immune escape of antibodies, including all clinical monoclonals, by advanced variants such as KP3.1.1. On average, over one-third of antibody epitope residues are mutated. These findings support pervasive immune escape, underscoring the need to effectively leverage multi-epitope-targeting strategies to achieve durable immunity. To support community accessibility, we developed an interactive web server for visualization and analysis of antibody-antigen complexes and mutational data.

SARS-CoV-2↗
PubMed2005

Immune escape phenotype of HPV16-associated tumours: MHC class I expression changes during progression and therapy.

Malignant transformation of somatic cells followed by selection of the transformed cell populations can give rise to tumours that display an immune escape phenotype, MHC class I deficient neoplasms. Experiments were designed to examine whether the immune escape phenotype of HPV16-associated tumours is stable or whether the MHC class I expression can change during tumour progression and therapy. It has been found that temporary growth of MHC class I- tumour MK16/1/IIIABC in syngeneic mice can lead to up-regulation of the low MHC class I expression, both in the subcutaneous tumour inocula and in their lung metastases. Mimicking this process in vitro by co-cultivation of tumour and spleen cell populations revealed that the spleen cells produce IFNgamma, which upregulates MHC class I expression on the MK16/1/IIIABC cells as well as their sensitivity to T cell-mediated cytolysis (CTLs). The up-regulation could be prevented by admixture of anti-IFNgamma antibody to the tumour/spleen cell mixtures. Similar up-regulation of the MHC class I expression was observed in HPV16-associated tumour cell lines, MK16/1/IIIABC, MK16/MET/M1, TC-1, TC-1/A9 and TC-1/P3C10 grown in vitro in the presence of IFNgamma. The up-regulation was found to be IFNgamma dose-dependent and the level of the MHC class I expression required for in vitro cytolysis of the tumour cells by CTLs could be characterized in cytofluorometry with anti-H-2 antibody. After removal of the IFNgamma from the cultivation medium or after injection of the IFNgamma-treated cells into syngeneic mice the MHC class I expression gradually dropped back to the original level or to the level observed on the tumours growing in vivo. These findings indicate that the immune escape phenotype of at least some HPV16-associated tumours is not stable and that up-regulation of the MHC class I expression can occur in vivo during progression of the MHC I- tumours, apparently due to production of IFNgamma by the immune cells in the tumour microenviroment and its vicinity. In vitro irradiation of HPV16-associated MHC class I-deficient tumour cell lines MK16/MET/M1 and TC-1/P3C10 with a dose of 150 Gy up-regulated their MHC class I expression. Similarly, substantial up-regulation of the MHC class I expression was observed in TC-1/A9 tumour recurrences after surgery. The up-regulation observed in the recurrences after surgery or after irradiation has reached the level required for in vitro cytolysis of the tumour cells by CTLs. If confirmed also with other tumour types and in human tumour systems, the up-regulation of MHC class I molecule expression during radiotherapy and in tumour recurrences after surgery may have important implications in the development of immunotherapeutic strategies.

Animals↗
PubMed2004

Adenovirus CD40 ligand gene therapy counteracts immune escape mechanisms in the tumor Microenvironment.

Tumors exhibit immune escape properties that promote their survival. These properties include modulation of Ag presentation, secretion of immunosuppressive factors, resistance to apoptosis, and induction of immune deviation, e.g., shifting from Th1- to Th2-type responses. These escape mechanisms have proven to hamper several immunotherapeutic strategies, and efforts need to be taken to revert this situation. We have studied the immunological effects of introducing CD40 ligand (CD40L), a potent dendritic cell activation molecule, into the tumor micromilieu by adenoviral gene transfer. For this purpose, a murine bladder cancer model (MB49) was used in C57BL/6 mice. The MB49 cells are known to induce IL-10 in the tumor environment. IL-10 potently inhibits the maturation of dendritic cells and thereby also the activation of CTLs. In this paper we show that CD40L immunogene therapy suppresses IL-10 and TGF-beta production (2-fold decrease) and induces a typical Th1-type response in the tumor area (200-fold increase in IL-12 production). The antitumor responses obtained were MB49 cell specific, and the cytotoxicity of the stimulated CD8(+) cells could be blocked by IL-10. Adenovirus CD40L therapy was capable of regressing small tumors (five of six animals were tumor free) and inhibiting the progression of larger tumors even in the presence of other escape mechanisms, such as apoptosis resistance. Furthermore, CD40L-transduced MB49 cells promoted the maturation of dendritic cells (2-fold increase in IL-12) independently of IL-10. Our results argue for using adenovirus CD40L gene transfer, alone or in combination with other modalities, for the treatment of Th2-dominated tumors.

Adenoviridae↗
PubMed2006

Epigenetic regulation of immune escape genes in cancer.

According to the concept of immune surveillance, the appearance of a tumor indicates that it has earlier evaded host defenses and subsequently must have escaped immunity to evolve into a full-blown cancer. Tumor escape mechanisms have focused mainly on mutations of immune and apoptotic pathway genes. However, data obtained over the past few years suggest that epigenetic silencing in cancer may be as frequent a cause of gene inactivation as are mutations. Here, we discuss the evidence that tumor immune evasion is mediated by non-mutational epigenetic events involving chromatin and that epigenetics collaborates with mutations in determining tumor progression. Since epigenetic changes are potentially reversible, the relative contribution of mutations and epigenetics, to the gene defects in any given tumor, may be a factor in determining the efficacy of treatments. We review new developments in basic chromatin mechanisms and in this context describe the rationale for the current use of epigenetic agents in cancer therapy and for a novel epigenetically generated tumor vaccine model. We emphasize that epigenetic cancer treatments are currently a 'blunt-sword' and suggest future directions for designing chromatin-based programs of potential value in the diagnosis and treatment of cancer.

Animals↗
PubMed1995

A family cluster of an immune escape variant of hepatitis B virus infecting a mother and her two fully immunized children.

A hepatitis B virus (HBV) immune escape variant which results from a substitution of glycine by arginine at position 145 (arginine-145) in the immunodominant neutralization epitope of the S protein was found to infect one child in a seroepidemiologic survey of 1,812 vaccinated children. The child's mother and a younger brother were also infected by the same HBV variant, despite a greater than accepted level of protective antibody (anti-HBV surface antigen) in both the index child (30 mIU/ml) and the brother (> 20,000 mIU/ml). Our findings suggest the perinatal or horizontal transmission of the arginine-145 HBV variant from mother to child, but the ability of this variant to propagate among the vaccinated children remains unknown.

Adult↗
PubMed2002

[The role of Fas/Fas ligand in tumorgenesis, immune escape, and counterattack in colonic cancer].

OBJECTIVE: To investigate the role of Fas/Fas ligand (FasL) in tum orgenesis, immune escape, counterattack in colonic cancer. METHODS: Fas and FasL were measured by immunohitochemistry in 52 colon cancer, 27 adenomas, 28 ulcerative colitis (UC), 30 normal colon tissues and 23 lymph node metastases of colon cancer. In different FasL expression regions, the apoptosis of tumor cells was detected by TUNEL. RESULTS: (1) The expression rate of Fas was lowest in colon cancer tissue. It was lower than that in adenomas and UC, while it was highest in normal tissue. Compare of Fas, FasL was highest in colon cancer tissue, lowest in the normal tissue. The FasL in adenomas and UC were higher than that in the normal tissue. (2)Expression of Fas/FasL was not correlated with the typ e of tumor histology, but it was correlated with Dukes'stage, tumor differentiation and lymph node metastasis.(3) In the same tumor tissue, FasL expression was not even. Apoptotic rate of tumor cells was higher in FasL positive region(n = 25)(81.2%) than that in FasL negative region(n = 25)(47.4%)(P < 0.01). (4) FasL was strong positive in all 23 lymph node metastases of large intestine cancer, and more than 75% tumor cells were FasL positive in each tissue. CONCLUSION: Fas/FasL play an important role in tumorgenesis, immune escape, counterattack in colon cancer.

Adenoma↗
PubMed1999

Membrane-bound Fas (Apo-1/CD95) ligand on leukemic cells: A mechanism of tumor immune escape in leukemia patients.

There is evidence from bone marrow transplantation that T cells may be involved in the immunologic control of leukemia. But many patients relapse despite a potent graft-versus-leukemia effect mediated by allogeneic T cells. The expression of the FasL protein has been suggested as a mechanism of tumor immune escape. We, therefore, evaluated the capacity of leukemic cells from patients with acute or chronic myelogenous leukemia to escape the allogeneic or autologous immune response by bearing the FasL molecule. Although almost all leukemic cells express the 37-kD form of FasL, only 54% of acute myeloblastic leukemia and 27% of chronic myeloid leukemia (CML) cells bore a FasL with killing properties, as assessed by the ability of leukemic cells to cause the apoptosis of a Fas-sensitive target cell line or autologous activated T cells in 3 tested leukemic cases. Experiments with a recombinant Fas-Fc molecule confirmed the role of Fas/FasL in leukemic-mediated cell death. Only CML leukemic cells from certain individuals contained the 26-kD truncated form of FasL. Thus, myeloid leukemic cells from some, but not all patients can set up a mechanism of immune escape involving the Fas/FasL pathway. This leukemic escape may have implications for patients eligible for adoptive cellular immunotherapy.

Cell Death↗
PubMed1999

Molecular and functional analysis of a conserved CTL epitope in HIV-1 p24 recognized from a long-term nonprogressor: constraints on immune escape associated with targeting a sequence essential for viral replication.

It has been hypothesized that sequence variation within CTL epitopes leading to immune escape plays a role in the progression of HIV-1 infection. Only very limited data exist that address the influence of biologic characteristics of CTL epitopes on the emergence of immune escape variants and the efficiency of suppression HIV-1 by CTL. In this report, we studied the effects of HIV-1 CTL epitope sequence variation on HIV-1 replication. The highly conserved HLA-B14-restricted CTL epitope DRFYKTLRAE in HIV-1 p24 was examined, which had been defined as the immunodominant CTL epitope in a long-term nonprogressing individual. We generated a set of viral mutants on an HX10 background differing by a single conservative or nonconservative amino acid substitution at each of the P1 to P9 amino acid residues of the epitope. All of the nonconservative amino acid substitutions abolished viral infectivity and only 5 of 10 conservative changes yielded replication-competent virus. Recognition of these epitope sequence variants by CTL was tested using synthetic peptides. All mutations that abrogated CTL recognition strongly impaired viral replication, and all replication-competent viral variants were recognized by CTL, although some variants with a lower efficiency. Our data indicate that this CTL epitope is located within a viral sequence essential for viral replication. Targeting CTL epitopes within functionally important regions of the HIV-1 genome could limit the chance of immune evasion.

Animals↗
PubMed2006

[Indoleamine 2, 3-dioxygenase activity in acute myeloid leukemia cells contributing to tumor immune escape].

This study was aimed to investigate the mechanism of indoleamine 2, 3-dioxygenase (IDO) activity in acute myeloid leukemia cells contributing to tumor immune escape. Myeloid leukemia cells were isolated from bone marrow of 23 patients with acute myeloid leukemia (AML) and IDO expression was detected by immunochemistry and RT-PCR methods. Then mixed lymphocyte reaction (MLR) of one way was carried out, leukemia cells were used as stimulating cells and T-lymphocytes were used as reactive cells in culture with or without 1-MT. T-lymphocyte proliferation rate was determined by MTT assay and IDO activity in supernatant of MLR was detected by high-performance liquid chromatography (HPLC). The results showed that IDO expression was found in 17 out of 23 cases of acute myeloid leukemia cells; IDO enzyme activity in leukemia cells inhibited T-lymphocyte proliferation in MLR cultures. It is concluded that IDO activity expressing in leukemia cells can suppress T-lymphocyte proliferation responses, which may be contributing to tumor immune escape.

Cell Proliferation↗
PubMed2003

[Experimental study on blocking immune escape of leukemia cells in the recipient after bone marrow transplantation].

OBJECTIVE: To investigate whether murine soluble Fas gene transfected marrow graft could block the immune escape of leukemia cells, so as to eliminate the residual leukemia cells and reduce relapse after bone marrow transplantation (BMT). METHODS: The murine leukemia/lymphoma models were established by inoculating female C57BL/6 mice (H-2b) with 10(5) EL4 cells/mouse through caudal vein. Donors of BM grafts were C57BL/6 male mice. Bone marrow mononuclear cells (BMMCs) were transfected with sFas or EGFP by adenovirus (adsFas or adEGFP) 24 hours before BMT (group D or E). The following three groups were set simultaneously: group A, no BMMCs transplanted; group B, BMMCs transplanted with no adenoviruses transfection; group C, EL4 cells transfusion only. Hematopoietic reconstitution, generation of leukemia/lymphoma and the survival rate were observed in all the groups after BMT. RESULTS: The spleen indices examined 11 days after BMT were not obviously different among group B, D and E (P > 0.05), but in group A were significantly lower than those in the groups B, D, E (P < 0.01). The leukocyte and platelet counts on day 30 after BMT were recovered in group B and D, but were very low in group C and E. The Y-chromosomes appeared 2 months after BMT. Bone marrow pictures in group B and D were almost normal, but in group C and E had plenty of lymphoblast-like tumor cells. Tumors were obviously revealed in the mice of group C and E by histopathology examination, but did not in group B and D. The survival rate was 0 in group A, 100% in group B and D, 12.5% in group C and 6.25% in group E. Compared with that in group E, the survival was significantly increased in the sFas group (P < 0.01). CONCLUSIONS: Graft transfected with sFas gene prolonged the post-BMT survival of leukemia/lymphoma mice. The transfection of sFas might block the effect of the immune escape of EL4 cells through FasL.

Animals↗
PubMed2006

An SopB-mediated immune escape mechanism of Salmonella enterica can be subverted to optimize the performance of live attenuated vaccine carrier strains.

Salmonellae have evolved several mechanisms to evade host clearance. Here, we describe the influence on bacterial immune escape of the effector protein SopB, which is translocated into the cytosol through a type III secretion system. Wild-type bacteria, as well as the sseC and aroA attenuated mutants exerted a stronger cytotoxic effect on dendritic cells (DC) than their SopB-deficient derivatives. Cells infected with the double sseC sopB, phoP sopB and aroA sopB mutants also exhibited higher expression of MHC, CD80, CD86 and CD54 molecules, and showed a stronger capacity to process and present an I-E(d)-restricted epitope from the influenza hemagglutinin (HA) to CD4+ cells from TCR-HA transgenic mice in vitro. The incorporation of an additional mutation into the sopB locus of the attenuated sseC, phoP and aroA mutants resulted in the stimulation of improved humoral and cellular immune responses following oral vaccination. The obtained results define a new potential immune escape strategy of this important pathogen, and also demonstrate that this mechanism can be subverted to optimize the immune responses elicited using Salmonella as a live vaccine carrier.

Animals↗
PubMed2006

Placenta-derived soluble MHC class I chain-related molecules down-regulate NKG2D receptor on peripheral blood mononuclear cells during human pregnancy: a possible novel immune escape mechanism for fetal survival.

Mammalian pregnancy is an intriguing immunological phenomenon where the semiallogeneic fetus is not rejected. Tolerance toward the fetus involves a number of mechanisms associated with modifications of the immune status of the mother. In this study, we strongly suggest a novel mechanism for fetal evasion of maternal immune attack, based on the engagement and down-regulation of the activating NK cell receptor NKG2D on PBMC by soluble MHC class I chain-related proteins A and B (collectively termed MIC). A similar immune escape pathway was previously described in tumors. We found that MIC mRNA was constitutively expressed by human placenta and could be up-regulated upon heat shock treatment. Our immunomorphologic studies showed that the MIC expression in placenta was restricted to the syncytiotrophoblast. Immunoelectron microscopy revealed a dual MIC expression in the syncytiotrophoblast: on the apical and basal cell membrane and in cytoplasmic vacuoles as MIC-loaded microvesicles/exosomes. Soluble MIC molecules were present at elevated levels in maternal blood throughout normal pregnancy and were released by placental explants in vitro. Simultaneously, the cell surface NKG2D expression on maternal PBMC was down-regulated compared with nonpregnant controls. The soluble MIC molecules in pregnancy serum were able to interact with NKG2D and down-regulate the receptor on PBMC from healthy donors, with the consequent inhibition of the NKG2D-dependent cytotoxic response. These findings suggest a new physiological mechanism of silencing the maternal immune system that promotes fetal allograft immune escape and supports the view of the placenta as an immunoregulatory organ.

Down-Regulation↗
PubMed2004

Immune escape and exploitation strategies of cytomegaloviruses: impact on and imitation of the major histocompatibility system.

Cytomegalovirus (CMV) has yielded many insights into immune escape mechanisms. Both human and mouse CMV encode a diverse array of gene products, many of which appear to modulate the immune response in the host. Some deflect the host response to infection and contribute to lifelong viral persistence while others exploit immune cells that respond to infection. Here, the viral functions that modulate and mimic host major histocompatibility complex (MHC) function will be reviewed. Viral gene products related to both classical and non-classical components of the MHC system assure the virus will persist in immunocompetent individuals. Examples of host countermeasures that neutralize viral immunomodulatory functions have emerged in the characterization of viral functions that contribute to this stand-off in CMVs that infect humans, other primates and rodents. CMV-induced disease occurs when the immune system is not yet developed, such as in the developing fetus, or when it is compromised, such as in allograft transplant recipients, suggesting that the balance between virus escape and host control is central to pathogenesis. Although evidence supports the dominant role of immune escape in CMV pathogenesis and persistence, MHC-related immunomodulatory functions have been ascribed only subtle impact on pathogenesis and the immune response during natural infection. Viral gene products that interface with the MHC system may impact natural killer cell function, antigen presentation, and T lymphocyte immune surveillance. Many also interact with other cells, particularly those in the myeloid lineage, with consequences that have not been explored. Overall, the virus-encoded modulatory functions that have been acquired by CMV likely ensure survival and adaptation to the wide range of mammalian host species in which they are found.

Adjuvants, Immunologic↗