TNF-alpha

Specific Immunosuppressive Therapy

July 20, 2016 Hematology, Immunology, Infectious Diseases, Oncology, Pharmacology, Transplantation No comments , , , , , , , , , , , , , , , ,

The ideal immunosuppressant would be antigen-specific, inhibiting the immune response to the alloantigens present in the graft (or vice versa alloantigens present in recipient in GVHD) while preserving the recipient's ability to respond to other foreign antigens. Although this goal has not yet been achieved, several more targeted immunosuppressive agents have been developed. Most involve the use of monoclonal antibodies (mAbs) or soluble ligands that bind specific cell-surface molecules. On limitation of most first-generation of mAbs came from their origin in animals. Recipients of these frequently developed an immune response to the nonhuman epitopes, rapidly clearing the mAbs from the body. This limitation has been overcome by the construction of humanized mAbs and mouse-human chimeric antibodies.

Many different mAbs have been tested in transplantation settings, and the majority work by either depleting the recipient of a particular cell population or by blocking a key step in immune signaling. Antithymocyte globulin (ATG), prepared from animals exposed to human lymphocytes, can be used to deplete lymphocytes in patients prior to transplantation, but has significant side effects. A more subset-specific strategy uses a mAb to the CD3 molecule of the TCR, called OKT3, and rapidly depletes mature T cells from the circulation. This depletion appears to be caused by binding of antibody-coated T cells to Fc receptors on phagocytic cells, which then phagocytose and clear the T cells from the circulation. In a further refinement of this strategy, a cytotoxic agent such as diphtheria toxin is coupled with the mAb. Antibody-bound cells then internalize the toxin and die. Another technique uses mAbs specific for the high-affinity IL-2 receptor CD25. Since this receptor is expressed only on activated T cells, this treatment specifically blocks proliferation of T cells activated in response to the alloantigens of the graft. However, since TREG cells also express CD25 and may aid in alloantigen tolerance, this strategy may have drawbacks. More recently, a mAb against CD20 has been used to deplete mature B cells and is aimed at suppressing AMR (antibody-mediated rejection) responses. Finally, in cases of bone marrow transplantation, mAbs against T-cell-specific markers have been used to pretreat the donor's bone marrow to destory immunocompetent T cells that may react with the recipient tissues, causing GVHD.

Because cytokines appear to play an important role in allograft rejection, these compounds can also be specifically targeted. Animal studies have explored the use of mAbs specific for the cytokines implicated in transplant rejection, particularly TNF-alpha, IFN-gamma, and IL-2. In mice, anti-TNF-alpha mAbs prolong bone marrow transplants and reduce the incidence of GVHD. Antibodies to IFN-gamma and to IL-2 have each been reported in some cases to prolong cardiac transplants in rats.

TH-cell activation requires a costimulatory signal in addition to the signal mediated by the TCR. The interaction between CD80/86 on the membrane of APCs and the CD28 or CTLA-4 molecule on T cells provides one such signal. Without this costimulatory signal, antigen-activated T cells become anergic. CD28 is expressed on both resting and activated T cells, while CTLA-4 is expressed only on activated T cells and binds CD80/86 with a 20-fold-higher affinity. In mice, D. J. Lenschow, J. A. Bluestone, and colleagues demonstrated prolonged graft survival by blocking CD80/86 signaling with a soluble fusion protein consisting of the extracellular domain of CTLA-4 fused to human IgG1 heavy chain. This new drug, belatacept, was shown to induce anergy in T cells directed against the graft tissue and has been approved by the FDA for prevention of organ rejection in adult kidney transplant pateints.

Fever

October 25, 2015 Infectious Diseases, Physiology and Pathophysiology No comments , , , , , , , ,

dreamstime_10999299high_feverBody Temperature System and Mechanisms could be found at thread "Mechanism of Thermoregulation" at http://www.tomhsiung.com/wordpress/2014/06/mechanism-of-thermoregulation/

Body temperature, at any given point in time, represents a balance between heat gain and heat loss. Body heat is generated in the core tissues of the body, transferred to the skin surface by the blood, and released into the environment surrounding the body.

The thermostat

In the hypothalamus there is a thermostat, which controls and maintains the temperature of the individual. If the thermostat has been reset to a new point different from the normal value, the body would sense the difference between true body temperature and the new thermostat via temperature receptors, and after the signal being transmitted into the hypothalamus, the ratio of heat production to heat loss will be changed accordingly via temperature-regulating responses to make the body core temperature the same as the new thermostat. For example, if the thermostat had been reset to above 37℃, the temperature receptors then signal that the actual temperature is below the new set point, and the temperature-raising mechanisms are activated. Then the ratio of heat production to heat loss would increases and the actual body temperature starts to increase until the value equaling the new set point.

Circadian

The body temperature of a health individual changes with circadian rhythm, with the lowest at 3 AM to 6 AM and highest at 3 PM to 6 PM. Generally a orally measured temperature higher than 37.2 C in the early morning or 37.7 in the late afternoon and evening is considered as fever.

Body temperature can be measured by several different methods and at many different sites. However, in critical ill patients the variability between sites may increase. For example, during open mouth breathing, sublingual temperature falls relative to tympanic membrane temperature. Likewise, skin temperature can fall relative to core temperature during cardiogenic shock due to a decrease in cutaneous blood flow. Because of this variability, mouth, skin, and axillary measurements are not recommended for use in critical ill patients.

Fever

Fever describes an elevation in body temperature that is caused by an upward displacement of the thermostatic set point of the hypothalamic thermoregulatory center. Many proteins, breakdown products of proteins, and certain other substances released from bacterial cell membranes can cause a change in the set point to rise. Fever is resolved when the condition that caused the increase in the set point is removed. Fevers that are regulated by the hypothalamus usually do not rise above 41 C, suggesting a built-in thermostatic safety mechanism.

Pyrogens are exogenous or endogenous substances that produce fever. Exgenous pyrogens are derived from outside the body and include such substances as bacterial products, bacterial toxins, or whole microorganisms. Exogenous pyrogens induce host cells to produce fever-producing mediators called endogenous pyrogens. When bacteria or breakdown products of bacteria are present in blood or tissues, phagocytic cells of the immune system engulf them. These phagocytic cells digest the bacterial products and then release pyrogenic cytokines (for information about inflammation mediators please refer to thread "Inflammation Mediators" at http://www.tomhsiung.com/wordpress/2015/03/inflammation-mediators/), principally interleukin-1 (IL-1), interleukin-6 (IL-6), interleukin-8 (IL-8), and tumor necrosis factor-alpha (TNF-alpha), into the bloodstream for transport to the hypothalamus, where they exert their action. These cytokines induce prostaglandin E2 (PGE2), which is a metabolite of arachidonic acid. It is hypothesized that when interleukin (IL-1B) interacts with the endothelial cells of the blood-brain barrier in the capillaries of the organum vasculosum laminae terminalis (OVLT), which is in the third ventricle above the optic chiasm, PGE2 is released into the hypothalamus.

At this point, PGE2 binds to receptors in the hypothalamus to induce increases in the thermostatic set point through the second messenger cyclic adenosine monophosphate (cAMP). In response to the increase in its thermostatic set point, the hypothalamus initiates shivering and vasoconstriction that raise the body's core temperature to the new set point, and fever is established.