Immunomodulation by immunopeptides and autoantibodies in aging, autoimmunity, and infection.

The operation of the immune system is a complex orchestration of specific self and non-self-recognition capacities mediated by cells of the innate system acting in coordination with T and B lymphocytes in a series of processes modulated by cytokines. We provide evidence for a natural immunomodulatory system involving autoantibodies directed against a controlling segment of T cell receptor Vbeta chains that downregulate production of stimulatory cytokines balanced by the peptides which in turn upregulate inflammatory activities mediated by TH1-type helper cells. TCR Vbeta-derived peptides effective in retrovirally induced immunosupression could also reverse the effects of immunosenescence in aged mice by restoring the balance of TH1- and TH2-type immunity and the resistance of the animals to cardiac pathology caused by infection with coxsackievirus. An unexpected finding was an adaptive role of the T cells from peptide-treated mice in remodeling damaged hearts by increasing net collagen synthesis by cardiac fibroblasts.

Immune control of coxsackievirus-induced cardiopathology.

Retrovirally induced acquired immunodeficiency in humans and mice induces immune dysregulation as well as increased oxidative stress as the disease progresses. Both immunodeficiency and oxidative stress make the host susceptible to the development of heat disease either by physiological changes or by the direct influence of cardiovirulance. Antioxidant supplementation has been shown to influence the onset as well as the degree of cardiopathology due to primary infections or co-infections. An alternative treatment is the use of peptide immunomodulatory therapy to enhance cytokine production, immune cell function and resistance to opportunistic infections. This review compiles our in vivo and in vitro studies on the effects of antioxidant supplementation and peptide therapy on the immune control of coxsackievirus induced cardiopathology in AIDS.

T-cell receptor-derived peptides in immunoregulation and therapy of retrovirally induced immunosuppression.

Retrovirally infected humans and mice showed progressive acquired immunodeficiency accompanied by the production of elevated levels of autoantibodies directed against T-cell receptor variable-domain epitopes. Epitope mapping analyses indicated that a major determinant recognized was defined by a 16-mer peptide containing the entire CDR1 segment and part of the FR2 region of human Vbeta8, and that both species showed reactivity to the same sequence. Either prophylactic or therapeutic administration of this peptide to retrovirus-infected C57/BL/6 mice normalized the balance of T(H)1- and T(H)2-type helper activity and restored the resistance to infection by the opportunistic parasite Cryptosporidium. Administration of the peptide did not generate significantly increased levels of autoantibody, but had a profound effect on T-cell activity as well as other aspects of inflammation, including NK-cell activity. A 16-mer derived from the Jbeta sequence showed similar functional effects on T cells from retrovirus-infected mice. Direct binding of the VbetaCDR1 peptide to recombinant TCR Valpha/Vbeta constructs, as well as to IgM natural autoantibodies, suggests that the cell surface receptor for the peptide is the alpha/beta TCR on T cells and surface IgM in B cells. The Vbeta CDR1 peptide stimulated division of murine splenocytes in vitro, stimulated the production of the T(H)1 cytokine IL-2, and synergized with the T-cell mitogen concanavalin A in proliferation and IL-2 production. These studies indicate that administration of peptides derived from T-cell receptor variable domains to animals immunosuppressed as a result of retroviral infection has a profound immunomodulatory effect enhancing overall T-cell functional capacity, particularly with respect to the cytokine production characteristic of T(H)1-type cells. Our studies are interpreted in the context of other recent investigations of immunomodulatory peptides.

Cocaine injection and coxsackievirus B3 infection increase heart disease during murine AIDS.

Coxsackievirus initiates myocarditis especially in the immunologically deficient or immature. To test whether Coxsackievirus B3 (CVB3) induced pronounced cardiomyopathy during severe immune dysfunction of murine AIDS, female C57BL/6 mice were infected with LP-BM5 retrovirus and superinfected with CVB3. Some were also injected daily with cocaine hydrochloride in 0.9% saline solution (30 mg/kg) intraperitoneally, because cocaine also suppresses cellular immune response. Heart tissue was analyzed histopathologically. Mice experiencing concurrent retrovirus and Coxsackievirus infection had a high degree of cardiac lesions consistent with myopathy compared with findings in uninfected animals (p <.05). Cocaine injection during murine retrovirus infection greatly exacerbated the pathogenesis of Coxsackievirus infection. C57BL/6 mice, essentially resistant to Coxsackievirus-induced cardiomyopathy, became susceptible during the immune dysfunction in murine AIDS. This suggests that retrovirus infection causes conditions favoring Coxsackie-induced cardiac lesions. Interleukin (IL)-2 and IL-4 expression by splenocytes from the dually infected retrovirus and Coxsackievirus group showed no significant differences when the animals were also cocaine treated. However tumor necrosis factor TNF-alpha production was significantly decreased in dually infected retrovirus + Coxsackievirus mice treated with cocaine, compared with findings in various controls (p <.05).

Immune dysfunction during alcohol consumption and murine AIDS: the protective role of dehydroepiandrosterone sulfate.

Acquired immune deficiency syndrome (AIDS) is a clinical disorder caused by the human immunodeficiency virus (HIV) after development of severe immunosuppressive changes. Chronic ethanol (EtOH) consumption accentuates the severity of murine AIDS (MAIDS). Because hormone production is often suppressed by chronic EtOH intake, as well as retrovirus infection, we investigated whether hormone supplementation during chronic EtOH consumption contributes to slowing immune dysfunction caused by LP-BM5 infection and/or EtOH use. Because dehydroepiandrosterone sulfate (DHEAS) was previously shown to have immune-enhancing properties during MAIDS, we determined whether DHEAS reduced cytokine dysregulation otherwise exacerbated by chronic EtOH intake during MAIDS. Adult female C57BL/6 mice were infected with LP-BM5 murine retrovirus. Some were fed 40% EtOH in drinking water and agar gel for 16 weeks postinfection. EtOH consumption further inhibited T- and B-cell proliferation beyond suppression due to retrovirus infection. Interleukin (IL)-2 release produced by concanavalin A-stimulated splenocytes was reduced by EtOH use by infected and uninfected mice. DHEAS overcame much of the effects induced by retrovirus infection and/or EtOH use. IL-4 secretion and IL-6 secretion were enhanced. Hepatic vitamin E levels were decreased by murine retrovirus infection, as well as by EtOH use in both uninfected and infected mice. In addition, DHEAS (0.01%) supplementation during MAIDS prevented the further dysregulation of cytokines and hepatic lipid peroxidation due to EtOH intake, partially restored T- and B-cell proliferation, and maintained hepatic vitamin E levels to near normal levels.