CD4+ T-helper

AIDS (acquired immunodeficiency syndrome) is the final stage of disease caused by infection with HIV. In this stage, the vims infection has severely affected the immune system, causing a depletion of CD4+ T-helper cells. AIDS is characterized by the manifestation of typical diseases caused by opportunistic infections (Pneumocystis carinii pneumonia, CMV retinitis, candidiasis of the esophagus, cerebral toxoplasmosis), neurological manifestations, cachexia, or certain tumors (Kaposi sarcoma of the skin, B-cell lymphoma). 

After this initial phase of infection subsides, the free viral load in the blood declines, often to almost undetectable levels. This latent phase may last for anything up to 10 years or more. During this phase, however, there does seem to be continuous synthesis and destruction of viral particles. This is accompanied by a high turnover rate of (CD4+) T-helper lymphocytes. The levels of these T-lymphocytes decline with time, as does antibody levels specific for viral proteins. The circulating viral load often increases as a result, and the depletion of T-helper cells compromises general immune function. As the immune system fails, classical symptoms of AIDS-related complex (ARC) and, finally, full-blown AIDS begin to develop. 

Lymphocytes, the effector cells of the acquired immune system, include morphologically indistinguishable T and B cells, the former divided into CD4+ T helper cells and CD8+ cytotoxic T cells. Since the functions of those cell subsets differ so drastically, it became important to develop tools to distinguish them from each other. Efforts to identify cell subsets according to their expression of different surface antigens have been successful, including various Cluster of Determination (CD) markers (Table 23.1). In addition, cross-reactive monoclonal antibodies, and subsequently developed species-specific polyclonal and monoclonal antibodies towards the major histocompatibility complex (MHC) have been used to label cells in circulation and in tissue sections (Table 23.1). 

Before consideration of the available methods, what is known of the immunobiological mechanisms of both forms of chemical allergy will be reviewed briefly. The development of immune responses, including allergic responses, is directed by the activity of CD4+ T helper (Th) cell subpopulations and their cytokine products. Two phenotypes... 

B cells are produced by the bone marrow. In response to activation of CD4+ T helper cells (see below), B cells proliferate and produce antibodies. (The term CD stands for cluster of differentiation. They are proteins coating cell surfaces. Altogether, there are more than 160 different types of CDs.) The antibodies produced by B cells circulate in the bloodstream and bind to antigens. Once bound, other cells are in turn activated to destroy the antigens. 

IL-2 is possibly the most-studied interleukin. It is also called T cell growth factor. IL-2 is a ISkDa glycoprotein produced by CD4+ T helper cells. It has 133 amino acids. There are four helical regions and a short )3-sheet section (Fig. 4.7). 

Hansen G, Mclntire JJ, Yeung VP, et al CD4+ T-helper cells engineered to produce latent TGF-(Jj reverse allergen-induced airway hyperreactivity and inflammation. J Clin Invest 2000 105 61-70. 

The induction of CD4+ T helper 1 responses suggests that IRIV could provide adjuvance to the generation of HLA class I-restricted CTL responses. Thus, we addressed the capacity of IRIV to enhance the induction of CTL specific for influenza matrix (IM) 58-66 epitope and Melan-A/Mart-127-35 melanoma-associated epitope. Briefly, CD 14-cells isolated from healthy donor s peripheral blood were cocultured with autologous iDC in presence of peptide and empty IRIV or in presence of peptide alone. 

AIDS, caused by the human immunodeficiency virus (HIV), represents the most dramatic example of viral-induced cell depletion (A6). The FasL of T cells in AIDS patients is upregulated by two HIV gene products Tat and gpl20 for the depletion of CD4 T helper lymphocytes (A6). Tat is secreted by HIV-infected cells and can penetrate noninfected T cells to upregulate FasL expression in the affected cells and may thus facilitate Fas-mediated apoptosis. In addition, gpl20 can sensitize T cells for CD95-mediated apoptosis (A6). 

AIDS represents the classic example of immunodeficiency disease caused by extrinsic factors, in this instance the human immunodeficiency virus (HIV). This virus exhibits a strong tropism for CD4 T helper cells these become depleted, giving rise to increased frequency of opportunistic infections and malignancies in infected individuals. AIDS is also characterized by an imbalance in THl and TH2 cells, and the ratios of cells and their functions are skewed toward TH2. This results in hypergammaglobulinemia, loss of cytotoxic lymphocyte activity, and delayed hypersensitivity. 

Spielings E, Vermeulen CJ, Vogt MH, Doemer LE, et al. 2003. Identification of HLA class II restricted H-Y-specific T-helper epitope evoking CD4+ T-helper cells in H-Y-mismatched transplantation. Lancet. 362 610-615. 

Williams, D.L., Asahi, H., Botkin, D.J. and Stadecker, M.J. (2001) Schistosome infection stimulates host CD4(+)T helper cell and B-cell responses againsta novel egg antigen, thioredoxin peroxidase. Infection and Immunity 69, 1 1 34-11 41. 

HIV is a member of the retrovirus family (see Table 34-1).32 HIV impairs the function of certain cells in the immune system such as CD4+ (T-helper) lymphocytes.11,26 Destruction of immune system components often leads to the severe immunocompromised state known as AIDS. This virus exists in at least two forms HIV-1 and HIV-2. Both forms of the virus are capable of causing AIDS, but HIV-1 is more prevalent.32 Hence, HIV-1 is also referred to informally as the AIDS virus. Because there is currently no effective way to kill the AIDS virus in humans, there is no cure for AIDS. 

The lipopeptide vaccine described in this study consists of a CD4+ helper T-cell epitope ([T]) and a B-cell epitope ([B]). These two epitopes are separated by a lysine residue (K) to which is attached the lipid moiety via two serine residues (Fig. IB). The CD4+ T-helper epitope KLIPNASLIENCTKAEL used is derived from the fusion protein of the morbillivirus canine distemper virus (34) and is recognized by T cells from BALB/c and C57BL6 mouse strains (4). The B-cell epitope is LHRH and has the sequence HWYSGLRPG. The presence of anti-LHRH antibodies can render vaccinated animals sterile. 

Cassataro, J., Estein, S.M., Pasquevich, K.A., et al. (2005) Vaccination with the recombinant Brucella outer membrane protein 31 or a derived 27-amino-acid synthetic peptide elicits a CD4+ T helper 1 response that protects against Brucella melitensis infection. Infect. Immun. 73(12), 8079-8088. 

As described above, peptide epitopes bound to MHC class I or II molecules are able to stimulate CD8+ and CD4+ T cells, respectively. Both CD4+ T-helper cells and CD8+ CTLs are critical to protective immunity and to vaccine efficacy. CD4+ T-helper cells play an important role in the development of memory B-cell (antibody) and memory CTL (cytotoxic T-cell) responses. CD4+ T-helper cells are also active against pathogens on their own. Therefore, CD4+ T-helper cells have been called the conductors of the immune system orchestra (14). CD8+ CTLs are able to directly kill infected target cells and thus are critical in the containment of... 

To counter the low success rate of B-cell epitope prediction, MHC class II epitopes for CD4+ T cells may be emphasized when antibody response is key in vaccine design. CD4+ T-helper cells are critical to induce the activation of B cells that produce antibodies. B-cell antigens that contain significant MHC class II epitopes may outperform B-cell antigens without cognate help. An identified T-cell epitope may sometimes contain a B-cell epitope. In addition, B-cell epitopes may colocalize near or overlap MHC class II epitopes (32, 33). 

Synthetic Glycopeptides Designed to Elicit a CD4" " T-Helper (Ty/) Response. 2677... 

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