Immune Defects and Immune Response Modulation

Immune defects are frequently acquired by therapy or viral infections, or as a consequence of advanced age. In rare cases immune defects can also result from congenital defects, these include severe combined immuno­deficiency's (SCID) or transient partial immune defects (mainly involving IgA responses). Immunomodulation can be attempted using interleukins or monoclonal antibodies directed against lymphocyte surface molecules or antigenic peptides. Immunostimulation is achieved using adjuvants or the genetically engineered insertion of costimulatory molecules into tumor cells. Immunosuppression can be induced globally using drugs, or specifi­cally using antibodies, interleukins or soluble interleukin receptors; this can also be achieved by means of tolerance induction with proteins, peptides, or cell chimerism.

Immune Defects

The most important and frequent immune defects are acquired, e.g., iatro­genic (cytostatics, cortisone, irradiation, etc.), age-induced, or the result of viral infections (above all HIV). Congenital defects are rare; examples include Bruton's X-chromosome-linked B-cell defect, thymic hypoplasia (DiGeorge), and combined T- and B-cell deficiency resulting from MHC defects (bare lymphocyte syndrome) or from enzyme defects (adenosine deaminase [ADA] deficiency or purine nucleoside phosphorylase [PNP] deficiency). These defects can also be repaired by reconstitution (thymic transplants), or in some cases through the use of stem cells (gene therapy; one of the very first successful gene therapies was the treatment of ADA deficiency). More frequent congenital defects involve selective deficiencies, for example a relative-to-absolute IgA deficiency, normally being more prominent in in­fants than later in life. Children with such deficiencies are more susceptible to infection with Haemophilus influenzae, pneumococci, and meningococci. General consequences of immune defects include recurring and unusual in­fections, eczemas, and diarrhea.

Immunoregulation

This area of immunology is difficult to define and remains elusive. Antigens represent the most important positive regulator of immunity; since there is simply no immune stimulation when antigens have been eliminated or are absent. Other important regulators include interferon gamma (IFNy) for TH1 responses, and IL-4 forTH2 responses. Further IL-dependent regulatory func­tions are in the process of being defined. The existence of specific CD8+ T sup­pressor cells, capable of downregulating immune responses, has been pos­tulated and their role was assumed to be that of counteracting the inflam­matory CD4+ T cell response. However, to date there has been no convincing proof of their existence. The term CD8⁺ T suppressor cells, which is used fre­quently, is therefore misleading and inaccurate. In relatively rare cases, cytotoxic CD8+ T cells do exercise a regulatory effect by lysing infected APCs or B cells. It is unclear whether CD4+ T cells could have similar effects. Regulation via idiotypic/anti-idiotypic antibody networks (i.e., anti­bodies directed against the ABS of other antibodies), or anti-TCR networks, have also been postulated—but remain hypothetical. Although attractive hypothesis, for most cases such regulatory pathways have only proved dis­appointing theoretical concepts, and as such should no longer be employed in the explanation of immunoregulation. In isolated cases, antiidiotypic, or anti-TCR peptide-specific feedback, mechanisms can be modeled under forced experimental conditions. However such conditions probably fail to model normal situations, therefore they cannot accurately indicate whether these feedback mechanisms have a role in regulating the immune system as a whole.

Immunostimulation

The aim of immunological treatment of infections and tumors is to enhance immune responsiveness via the use of thymic hormones (thymopoietin, pen-tapeptides), leukocyte extracts, or interferons. Derivatives or synthetic ana­logs of microorganisms such as BCG, components of Corynebacteriumparvum and peptidoglycans (e.g., muramyl peptide), or oligonucleic acids (CpG), are used as adjuvants. Components of streptococci and Streptomyces, eluates and fractions of bacterial mixtures, and the related synthetic substance levami-sole are also used. The role of Toll-like receptors in these adjuvant effects is becoming increasingly understood, with a major role of these molecules being to link non-specific innate resistance to specific immunity. .

Recently developed immune therapy strategies aim to improve antigen presentation. For instance interleukins, or costimulatory molecules such as B7 or CD40, have been inserted into tumor cells by means of transfection. Hybrid antibodies have been constructed in an attempt to improve antigen recognition and phagocytosis (one such example is the coupling of an anti- CD3 antibody with tumor antigen-specific antibodies). Other ideas tested successfully in model experiments include systemic treatment with interleu­kins (this presents with frequent toxicity problems) or targeted insertion of GM-CSF, TNF, or IL-2. Alternatively, the production of IFNγ or IFNβ by cells, or the use of molecules capable of polyclonal T- and B-cell stimulation has been employed. This concept utilizes local chronic or acute infections with the aim of achieving inflammation surrounding, or direct infection of, tumor cells re­sulting in their cytolytic destruction. Such concepts have also been used to force phagocytosis and uptake of antigens by APCs with the aim of inducing or enhancing tumor immunity (e.g., BCG infections in bladder carcinoma treatment).

Immunosuppression

Various methods are employed to inhibit, or suppress, the immune response:

-Generalized immunosuppression; glucocorticoids (inhibition of inflam­matory cells), cytostatic drugs (endoxan, DNA alkylating agents, methotrex­ate, antimetabolites), and more specific immunosuppressants, e.g., cyclosporine A, FK506, rapamycin (inhibition of signal transduction in T cells).

-Immunosuppression by antibodies, soluble cytokine receptors, deletion of T cells or T-cellsub-populations (anti-CD4, anti-CD8, anti-CD3, anti-Thy1, etc.). Administration of monoclonal antibodies directed against adhesion mo­lecules and accessory molecules or cytokines and cytokine receptors. Admin­istration of soluble cytokine receptors, or soluble CTLA4, in order to block B7- and B7-2 (important costimulators,).

-Specific tolerance induction or “negative immunization.” Massive and de­pletive T-cell activation brought about by systemic administration of large amounts of peptides, proteins (risk of immunopathology), or cells (chimer- ism).

-Complete neutralization and elimination of the antigen with the purpose of preventing induction of an antibody response. Example; rhesus prophy­laxis with hyperimmune serum.

Adaptive Immunotherapy

This involves in-vitro antigen stimulation, and consequent proliferation, of patient T-cell effector clones or populations (CD8+ T cells or less specific lymphokine-activated killer cells, LAK cells), followed by transfusion of these cells back into the patient. This method is sometimes used as a means of limiting cytomegaly or Epstein-Barr virus infection of bone marrow recipients. The LAK cells also include less specific NK-like cells, which can be expanded with IL-2 in the absence of antigen stimulation.

Toxic antibodies are monoclonal antibodies to which toxins have been coupled. These are used as specific toxin transporters, administered directly, or with liposomes bearing anchored antibodies and containing a toxin or cytostatic drug.

References

Zinkernagel, R. M. (2005). Medical Microbiology.