Table 5.
Other Immunomodulators, Including Unintended Immune Consequences of Husbandry and Environmental Factors, Clinical and Experimental Interventions
| Immunomodulators | Possible Effects on the Immune and Other Systems | References |
|---|---|---|
| Environmental factors | ||
| Housing conditions | ||
| Caging | Individual ventilated cages (compared to static microisolator caging): decreased bioburden and risk of intercage infection spread; increased cold stress; decreased circulating leukocytes; decreased intracage ammonia levels and correlated nasal pathology. | 322–325 |
| Bedding | Experimentally relevant parameters influenced by the type of bedding: higher intracage ammonia levels with reclaimed wood pulp bedding; corncob bedding associated with decreased efficiency of feed conversion in mice fed a high-fat diet; hepatotoxicity associated with vermiculite and unbleached pulp from pine and eucalyptus; hepatic and mammary carcinogenesis associated with aromatic red cedar bedding; altered estrogen signaling mainly due to BPA residues; corncob bedding associated with increased aggressivity and social stress in females; drastically lower endotoxin levels and bioburden associated with paper bedding. | 323,342,352–357,366 |
| Single or group housing and social stressors | Group housing: negative social events associated with lower lymphocyte proliferation; lower level of antigen-specific IgG; granulocytosis; lymphopenia, higher predisposition to tumor development and progression, huddling associated with amelioration of cold stress. | 326–330 |
| Individual housing: decreased antibody production; worsened allergic skin reaction; increased cold stress. | ||
| Environmental enrichment | Reduced stress levels; reduced oxidative stress; enhanced NK antitumor functions; enhanced macrophage chemotaxis and phagocytosis; improved capacity to clear systemic microbial infection; enhanced lymphocyte chemotaxis and proliferation; increased lifespan. | 331–336 |
| Temperature and humidity | Thermoneutral housing temperature (26°–34°C): reduced tumor formation, growth rate and metastasis due to increased CD8+ T cells; reduced myeloid-derived suppressor cells and Tregs. | 327,328,337–341,473–476 |
| Sub-thermoneutral housing temperature (20°–26°C): suppressed immune responses; increased therapeutic resistance of tumor and GVHD severity; suppressed myeloid cells function; alternative activation of macrophages. | ||
| Elevated humidity: increased bioburden; high ammonia levels due to expansion in urea-converting microflora. | ||
| Environmental noise and vibration | Altered tumor resistance; immunosuppression; reduced body weight; reduced fertility. | 348–351,477 |
| Inappropriate handling; untrained personnel | Increased risk of infection associated with inappropriate PPE and insufficient sterilization of equipment; pain, discomfort and stress associated with frequent/improper handling. | 316 |
| Altered light-dark cycle | Suppressed immune response; decreased splenic T cells; continuous illumination associated with decreased CD8+ and CD4+ cells in thymus and lymph nodes. | 343–345 |
| Dim lights | Elevated nighttime light exposure in male mice associated with worsened inflammation and weight gain under high-fat diet regimen. | 478 |
| Diet and water modifications | ||
| Caloric restriction | Immune effects: reduced H2O2, TNF α, IL6, IL2, IL10, NO, IFNγ; decreased macrophage activation; impaired NK cell function; reduced IgA in small intestine and serum IgG. | 363,478–483 |
| Other effects: increased lifespan; reduced age-related morbidities. | ||
| Protein-energy malnutrition | Impaired proliferation CD8+ T cells; modulation of intestinal IgA responses to rotavirus; increased duodenal γδ IELs; increased production of jejunal proinflammatory cytokines in response to bacteria. | 484–486 |
| Prolonged fasting (48–120 h) | Stress response due to activation of hypothalamic-pituitary-adrenal axis; thymic atrophy (apoptosis of cortical DP thymocytes). | 487 |
| High-fat diet (in C57BL/6 mice) | Suppression of delayed hypersensitivity; altered intestinal microbiota with stimulation of mucosal immunity; altered systemic metabolomes; inflammation of adipose tissue with release of adipokines, cytokines, and chemokines, and propagation of a chronic inflammatory state (inflamobesity). | 488–490 |
| Chlorella vulgaris supplementation | CYP-treated mice: reinstated lymphocyte proliferation and macrophage phagocytic activity; stimulation of IL2, IL12, TNFα, IFNγ, NK cell cytotoxicity; decreased splenic necrosis. | 491 |
| Polyunsaturated fatty acids supplementation | Dietary DHA and AA associated with improved allergen-induced dermatitis as consequence of increased FoxP3+ T cells, elevated IL10, and decreased TNFα. | 492 |
| Water acidification | Switch from normal tap water to acidified water associated with severe and long-lasting stress. | 343 |
| Nutritional deficiencies | ||
| Zinc deficiency | Thymic atrophy (loss of DP thymocytes); accelerated lymphopenia with loss of antibody and cell-mediated responses; decreased number of pre-B cells, better survival for pro-T cells and mature DP and CD8+ T cells; increased myeloid lineage in bone marrow. | 493–496 |
| Vitamin A deficiency | Decreased ILC3 and antibacterial responses; compensatory expansion in IL-13-producing ILC2 and increased anti-helminth responses; intestine devoid of CD4+ and CD8+ T cells; lower salivary IgA levels and increased serum IgG response in mouse model of influenza; decreased mucosal antigen-specific IgA responses. | 497–499 |
| Vitamin D deficiency | VDR-deficient mice: increased mature DCs in skin draining lymph nodes; decreased Th1-cell responses and induction of IL10-producing Tregs. | 500 |
| Diet and water contaminations | ||
| Estrogenic endocrine-disruptors | Isoflavones (genistein): thymic atrophy; suppression of delayed hypersensitivity; decreased splenic NK cells; decreased IFNγ in response to bacterial infection. | 365,366,501–503 |
| Mycotoxins (aflatoxins, deoxynivalenol, zearalenone): elevated IgA and IgE; kidney mesangial IgA deposits; polyclonal activation of IgA secreting cells; IgA autoantibody. | ||
| BPA (cages, water bottles): lupus-like syndrome (C57BL/6 mice); allergic airway disease (BALB/c mice). | ||
| Halogenated aromatic hydrocarbons (PCDFs;PCDDs) | Contaminated food and bedding: inhibited innate and adaptive immune responses; atrophy of lymphoid organs; TCDD targets thymic lymphoblasts. | 364,504,505 |
| Metals (As, Cd, Pb, Hg, Se) | Complex immune-modulating effects (immunosuppression and immunostimulation). | 504,506 |
| As: decreased DCs in mediastinal lymph nodes of influenza A-infected C57BL/6 mice. | ||
| Microbial status, pathogens, and biosecurity | ||
| MHV | MHV-3-infected C57BL/6: impairment of pre-B cells maturation and B cells functions. | 507–509 |
| A59-infected BALB/c: transient lymphocyte apoptosis in the thymus. | ||
| MHV-JHM-infected BALB/cByJ: functionally altered CD4+ and CD8+ T cells, and APCs. | ||
| Sendai virus | Interference with macrophage and their phagocytic activity, NK cells, and T and B cell function; increased isograft rejection. | 507,510–513 |
| MNV | Lethal infection in mice deficient for STAT1 and IFN receptors; alteration of immune/inflammatory parameters in diverse mouse models including Mdr1a deficient animals infected with Helicobacter bilis interfering with dendritic cell function and cytokine responses; infection of wild-type mice associated with mild intestinal inflammation, splenic red pulp expansion, and white pulp activation. | 514–516 |
| MuHV-1 | Loss of splenic T and B cells; interference with key coordinating role of DCs; functional impairment of macrophages and loss of response to cytokines; altered responses to mitogens, antigens, increased allograft rejection, delayed type hypersensitivity responses, and clearance of other pathogens; formation of anti-cardiac autoantibodies. | 440,517–520 |
| MuHV-3 | Thymic necrosis (specific targeting of CD4+ T cells in newborn mice); autoimmune gastritis in BALB/c and A strain; autoimmune oophoritis and production of antibodies to thyroglobulin. | 413,440,521 |
| MPV | Suppressed proliferation (spleen, popliteal lymph node), increased proliferation (mesenteric lymph node) in ovalbumin-primed mice; altered alloreactive T cells and abnormal CD8+ T cell rejection of tumors and skin allografts (BALB/c); rejection of syngeneic grafts. | 522,523 |
| MVM | MVM: oncolytic, cytotoxic, replicative cancer inhibitor; deregulation of the Raf signaling cascade. | 415,524 |
| MVMi: depressed myelopoeisis in neonatal BALB/c; depletion of hemopoietic precursors, leukopenia, and compensatory erythropoiesis in adult and neonate SCID mice. | ||
| Murine retroviruses | Insertional mutagenesis (with reintegration of endogenous retroviruses or transposition of retroelements): immune relevant mutation such as Foxn1nu, Lepob, Faslpr. | 439–443,448,525–529 |
| Endogenous retroviruses in pancreatic islets: contribution to immune-mediated insulitis NOD mice. | ||
| LP-BM5-infected C57BL/6 mice: lymphadenopathy, splenomegaly; hypergammaglobulinemia; T and B cell dysfunctions; late appearance of B cell lymphomas; opportunistic infections. | ||
| LCMV | LCMV disease: all pathological alterations following infection are immune-mediated; prototype for virus-induced T-lymphocyte-mediated immune injury and for immune complex disease; protection from LCMV-induced disease conferred through immunesuppression; noncanonical type I IFN signaling responsible for lethality in LCMV-infected Stat1 deficient mice. | 530–532 |
| MHV-68 | Experimental infections of laboratory mice to study the pathogenesis of human lymphoproliferative disorders associated with EBV. | 422,426–430 |
| Bacteria | Mortality/morbidity (sepsis) in immune deficient mice: Pseudomonas aeruginosa, Klebsiella spp., E coli; potentially any bacteria in severely immunocompromised mice. | 375,378,381,440,451,533 |
| Abscesses: Staphylococci, Pasteurella pneumotropica. | ||
| Skin disease/morbidity: Corynebacterium bovis, Staphylococci. | ||
| Mycoplasma arginini: suppurative arthritis in Prkdcscid mice inoculated with contaminated cell lines. | ||
| Fungi | Pneumocystis murina: respiratory disease and mortality in immunodeficient mice. | 378,381,534–536 |
| Candida spp.: recent reports associated with immune deficiency/suppression and or use of antimicrobials. | ||
| Biosecurity in immunodeficient mice | High risk of Pneumocystis carinii infection in T cell-deficient mice including Foxn1nu, Prkdcscid mice and immune impaired GEMs; immunodeficient traits in mutant mice masked by the immune/inflammatory response associated with chronic γ-herpesvirus infection; MNV infection in Atg16l1-deficient mice associated with Paneth cell abnormalities; murine papillomavirus associated with proliferative lesions at the mucocutaneous junctions of Foxn1nu mice; mousepox recrudescence following immunosuppression and transmission to naïve mice. | 375,400,537–540 |
| Biosecurity: contaminated biologicals | Rodent pathogens (latent infections): contaminated serum with mousepox. | 378,410,434,451,452,541 |
| Human pathogens: contaminated human cell lines (humanized mice and patient derived xenografts mice). | ||
| Mycoplasma arginini: suppurative arthritis in Prkdcscid mice (contaminated cell lines). | ||
| Modulation of the microbiome | SFB associated with the development of IL17 and IL22-producing CD4+ T cells (TH17 cells) in the intestinal lamina propria of germ-free mice. | 386,387,405,406 |
| Tritrichomonas muris: associated with elevated TH1 response in the cecum of naive WT mice and accelerated colitis in Rag1-deficient mice after T cell transfer. | ||
| Drugs administered for clinical or experimental purposes | ||
| Tamoxifen-inducible Cre/loxP system (Cre-ERT2) | Estrogen-dependent and -independent tamoxifen immunomodulatory effect; shift from a TH1- to a TH2-mediated immune response. | 458,459 |
| Tetracycline/doxycycline-inducible Tet-Off/Tet-On system | Doxycycline-dependent modulation of immune and inflammatory functions including allotransplant rejection, response to LPS, neutrophil chemotaxis; tetracycline/doxycycline-induced dysbiosis. | 461,462,472 |
| Nitrosamines, nitrates, nitrites (mutagens, carcinogens) | DMN: suppression of both humoral and cell-mediated immunity. | 542–544 |
| ENU: lymphoma (AKR/J, C58/J, C57BL/6J, NOD/LtJ); myeloid malignancies (SWR/J, DBA/2J); thymic lymphoma with/without K-ras mutations. | ||
| TMP-SMX | TMP-SMX alone: no effect on hematopoiesis or immune cell functions. | 545 |
| TMP-SMX synergized with zidovudine: anemia, thrombocytopenia, lymphopenia, and neutropenia, decreased splenic macrophages, suppressed AC-dependent T cell responses. | ||
| Ivermectin | Immunomodulation of T-helper cells; decreased recruitment of immune cells and cytokines in a model of asthma; unintended activation of tamoxifen-regulated Cre fusion protein in T cells. | 460,546,547 |
| Estrogens (for engraftment of estrogen-dependent tumors) | Increased splenic neutrophils (estrogen-treated C57BL/6 mice); enhanced IFNγ expression; thymic atrophy (DERKO mice); myelosuppression (decreased pluripotent hematopoietic stem cells). | 501,548–552 |
| Synthetic estrogens (DES): altered thymic T cell differentiation through interference with positive and negative selection processes in prenatally exposed mice; functionally defective NK cells and increased tumor susceptibility in neonatally exposed female mice. | ||
| Other: increased trabecular bone mineral density, fat reduction and increased uterine weight (DERKO mice); fibro-osseous lesions (bone marrow replacement by fibrovascular stroma (KK/HlJ and NZW/LacJ female mice). | ||
| Androgens (for engraftment of androgen-dependent tumors) | Androgen stimulation: thymic involution resulting from decreased colonization of bone-marrow-derived stem cells; loss of thymic epithelial cells; thymocyte apoptosis; inhibition of CD4+ T cell differentiation through upregulation of phosphate Ptpn1; erythroid hyperplasia. | 553–556 |
| Castration: enhanced CD8+ T cell vaccine response to prostate-specific antigens. | ||
| Streptozotocin | Early lymphopenia in both blood and spleen; relative increased Tregs in spleen, peripheral blood, and lymph nodes; delayed islet and skin allograft rejection. | 557 |
| NPs | Suppression of systemic humoral immunity (multi wall carbon nanotubes); inhibition of T cell-mediated immunity (iron oxide NPs, fuellerene 60); myelosuppression (Sb2O3, Co, ZnO, TiO2 NPs); allergic reactions (Ag NPs); anti-inflammatory activity and inhibition of cellular responses induced by IL1B (citrate-coated gold NPs). | 558–563 |
| Other experimental interventions | ||
| Cre/loxP | Activation of STING antiviral response by endonuclease activity of Cre recombinase. | 457 |
| CRISPR-Cas9 | Adaptive immune response against Cas9. | 458,459 |
| Tetracycline/doxycycline-inducible Tet-Off/Tet-On system | Apoptotic response in activated lymphocytes resulting from DNA binding by tTA/rtTA. | 464 |
| Classical reporter molecules | Increase in the CTL response against transplanted eGFP-expressing leukemia cells in BALB/c mice; IFNγ response to the dominant CTL epitope of Luc, with consequent restricted growth and metastatic activity of the reporter-labelled tumor cells in a mouse model of mammary adenocarcinoma; antigen specific activation of T cells to the reporter gene β-galactosidase, with loss of transgene expression. | 465–470,564,565 |
AA, arachidonic acid; AC, accessory cell; BPA, Bisphenol A; CTL, cytotoxic T lymphocyte; CYP, cyclophospharmide; DCs, dendritic cells; DERKO, double ER knockout mice; DES, diethylstilbestrol; DP, double positive; DHA, docosahexaenoic acid; DMN, dimethylnitrosamine; EBV, Epstein-Barr virus; eGFP, enhanced green fluorescent protein; ENU, N-ethyl-N-nitrosourea; GVHD, graft-versus-host disease; IBD, inflammatory bowel disease; IELs, intra-epithelial lymphocytes; ILC3, type 3 innate lymphoid cells; ILC2, type 2 innate lymphoid cells; LCMV, lymphocytic choriomeningitis virus; Luc, luciferase; MHV, mouse hepatitis virus; MHV-68, murine gammaherpesvirus 68; MNV, murine norovirus; MNM, minute virus of mice; MPV, mouse parvovirus; MuHV-1, murid herpesvirus 1 (mouse cytomegalovirus); MuHV-3, murid herpesvirus 3 (mouse thymic virus); NKs, natural killer cells; NPs, nanoparticles; PPE, personal protective equipment; rtTA, reverse tetracycline-controlled transactivator protein; SFB, segmented filamentous bacteria; TCDD, 2,3,7,8-tetrachlorodibenzodioxin; TMP-SMZ, trimethoprim/sulfamethoxazole; Tregs, regulatory T cells; tTA, tetracycline-controlled transactivator protein; VDR, vitamin D receptor.