Succimer(DMSA) causes immune suppression & Persistent Infections by Organ System

[Guest guest]

This could be why some seem to improve on chelation and also why many of

these children don't do as well. I've included a section below on all the

viruses that could have a field day due to this type of immune suppression.

Cheryl

What should I avoid while taking succimer?

• Succimer can lower the activity of the immune system making you more

susceptible to infection. Avoid contact with people who have colds, the flu,

or other contagious illnesses. Contact your doctor immediately if you

develop signs of infection such as fever, sore throat, or coughing.

Commonly Used Therapy For Lead Poisoning Might Alter The Immune System,

Cornell Animal Study Indicates

ITHACA, N.Y. -- A commonly used drug for reducing toxicological effects of

lead poisoning might alter immune function, a Cornell University study of

pregnant rats and their offspring has found.

The drug is Meso-2,3-dimercaptosuccinic acid (DMSA), also known as succimer.

DMSA is currently the only approved medication in the United States for

children with high levels of lead.

Reporting in the current issue of the journal Toxicology (Vol. 132, No. 1,

pages 67-79), the researchers say it is not known if the so-called chelation

therapy has the same side effects in humans as was observed in rats. " Our

study and previous studies prove that DMSA can do what it's supposed to. It

chemically binds with lead in the recipient and gets that poison out of the

body, " says Rodney R. Dietert, the Cornell professor of immunotoxicology who

led the study.

" We knew that lead harms the immune systems of rats, humans and other

animals, but no one had ever looked at DMSA's effects on the fetal immune

system. This study provides the first evidence suggesting that DMSA

chelation therapy could have problematic side effects for the developing

immune system. "

------------------------------------------------------------------

The child taking succimer will need a complete blood count with

differential, direct platelet count, and serum transaminase levels before

chelation begins, and then once a week during treatment. The most common

side effects are mild vomiting, diarrhea, and rashes. Some patients develop

mild to moderate neutropenia. One in 10 develops mild liver enzyme

elevation.11

--------------------------------------------------------------------------------

Chelation Therapy and Neuropsychological Development in Children Exposed to

Lead

In a randomized trial, children with blood lead levels of 20 to 44 µg per

deciliter were assigned to receive either succimer, a chelating agent, or

placebo. Treatment with succimer reduced the blood lead levels, but after 36

months, when the children were about five years old, there were no

statistically significant differences between the two groups in IQ scores,

scores on a behavioral index, or scores on tests of neuropsychological

development.

This carefully controlled study found no benefit from lead-chelation therapy

in children. With succimer treatment, there were trends toward slightly

worse outcomes with respect to intelligence, behavior, and linear growth.

Chelation therapy cannot be recommended for children with moderate blood

lead levels

http://content.nejm.org/this_week/344/19/index.shtml

--------------------------------------------------------------------------------\

-----------------------------

Q. What were the risks of the medication for those in the non-control

group?

A. The parents were advised that there could be short term side effects

such as nausea, vomiting, diarrhea, skin rash or mild to moderate

neutropenia (low white blood cell counts which could lead to infection).

Q. Taking all of these factors together, was the study appropriately

designed to protect all the subjects (treated patients and placebos) to the

maximum extent possible while allowing this important inquiry to proceed?

A. Yes. Both the non-control and control groups received information on

their blood levels and vitamin/mineral treatment they would not otherwise

have received. Their homes were inspected and cleaned. Their participation

allowed the efficacy of the medication to be tested.

The results of the research study showed that the succimer did not have a

long term positive impact on preventing lead-induced changes in growth,

development and behavior. Although some might say this result proved that

the research was a failure, just the opposite is true. The research was a

success in that this form of treatment was not proven to be effective. Only

by performing this type of controlled research study were the researchers

able to make this important finding.

If one did not have this type of controlled study, this medication may have

been given to thousands of children — exposing them to the known side

effects on the hope it might help — with no study to prove its effect, one

way or the other.

http://www.hopkinsmedicine.org/press/2001/SEPTEMBER/TLC.htm

--------------------------------------------------------------------------------\

------------------------------------

Persistent Infections by Organ System

Immune System

A number of viruses can infect cells of the lymphoid system during acute

infection, and some of these viruses persist (Table 46-2). Thus, the

lymphoid system also may serve as a reservoir for seeding other organs with

the persisting virus. Persistent infection of the immune system may lead to

evasion of immunologic surveillance.

Human T-Cell Leukemia Viruses

Infection by these viruses is followed by a 10- to 30-year clinically latent

period before development of leukemias or neurologic disorders in a minority

of infected individuals. The expression of viral genes is regulated at the

level of transcription by the interplay of various cellular transcription

factors (CREB, ATF-2) and HTLV regulatory proteins (e.g., Rex, Tax).

Infected T cells expressing HTLV proteins are eliminated by the immune

system. The few cells containing truly latent provirus escape the immune

surveillance because HTLV expression is efficiently down regulated as a

result of DNA methylation and a lack of protein-protein (Tax-CREB)

interaction or appropriate transcription factors in quiescent T cells.

Epstein-Barr Virus

After the initial EBV infection and replication in epithelial cells (e.g.,

pharynx, salivary glands), the virus persistently infects hematopoietic

cells. It has been demonstrated that EBV persists in the peripheral blood of

all seropositive individuals, in CDIg+, CD23 and CD80 (B7) B cells. In these

cells, the virus is truly latent, but when it is reactivated, infectious

immortalizing virus is produced. The estimated frequency of EBV-carrying

cells in healthy individuals varies from 20 to 600 per 107 B cells.

Immortalized B cells obtained by in vitro infection of normal cells are a

well-studied model for latent EBV infection. These cells are phenotypically

lymphoblasts, expressing EBV-encoded latent proteins, six in the nucleus

(Epstein-Barr nuclear antigens) and three in the membrane (LMP1, LMP2A,

LMP2B). EBV-seropositive healthy individuals maintain humoral and cellular

immunity against these latent proteins, suggesting that immortalized EBV

lymphoblasts can occur and persist for long periods of time in vivo.

Since virus-specific antigens are present in the membrane of latently

infected B cells, it is appropriate to examine how these cells escape immune

surveillance. These cells were not killed by MHC-matched, virus-specific

cytotoxic lymphocytes (CTLs) in assays in which EBV-transformed B

lymphoblastoid cells derived from the normal B cells of the patients were

readily lysed. Resistance of these cells to CTLs is correlated with a

reduced level of the cellular adhesion molecules LFA-3 and ICAM-l on the

cell surface (Fig. 46-3). Therefore, the initial interaction that normally

occurs between CTLs and target cells does not take place, and the infected

cells may survive, even though they express class 1 major histocompatibility

complex molecules and the EBV-encoded latent membrane proteins.

Human Cytomegalovirus

The strongest evidence for the existence of latent CMV infection comes from

the increased incidence of reactivated infection in seronegative individuals

who undergo transplants of organs from seropositive donors or in

immunosuppressed AIDS patients. CMV is well known to infect multiple organs,

including the salivary glands, lung, gastrointestinal tract, kidney, liver,

spleen and brain. However, all the cell populations that harbor latent CMV

have not been adequately defined. The best candidate cells for latent

infection are thought to be monocytes.

The physical state in which CMV (DNA) persists appears to be episomal, and

it is transcriptionally silent or the extent of DNA expression is restricted

to immediate early (IE) genes. The CMV-host cell relationship appears to be

distinct relative to other herpesviruses such as HSV, VZV or EBV. During

persistence CMV appears to impair immune responses at several levels: a)

altered expression and intracellular distribution of antigen-presenting

molecules such as MHC class I; altered production of lymphocyte adhesion

(e.g., ICAM-1, LFA-1) or co-stimulatory molecules (e.g., B7); c) inhibition

of complement-mediated lysis due to an increased production of inhibitory

factors (e.g., CD55); d) masking of the cell surface with overproduction of

Fc receptors that are able to bind IgG, thus preventing immune lysis; e)

excretion of immune modulators (e.g., TGF beta, TNF alpha) by CMV-infected

cells; f) CMV encodes G protein coupled receptors that resemble cellular

molecules and through molecular mimicry may escape immune recognition.

Human Herpesviruses 6 and 7

These viruses (HHV-6A, HHV-6B and HHV-7) persistently infect 7090% of the

human population. They are identified as CD4+ T-lymphotropic viruses. HHV-6

and HHV-7 replicate well and can be isolated from PBMCs. In addition, both

viruses are often detected in saliva. It is not precisely known what cells

in the body become latently infected and/or produce infectious virus. Also,

both viruses are reactivated in individuals receiving immunosuppressive

therapy or with immune disorders, such as AIDS.

Nervous System

Many chronic, degenerative nervous system diseases are related to viral

persistence (Table 46-3). Persistence in the nervous system probably

involves some unique mechanisms that take advantage of the many types of

specialized cells and the immunologically privileged status of the central

nervous system.

Herpes Simplex Virus Types 1 and 2

During acute herpes simplex virus (HSV) infection (see Ch. 68), virus and/or

viral components (e.g., nucleocapsids) containing viral genetic material

ascend in nerve axons from the initial site of infection to the sensory

gangliamainly the trigeminal ganglia HSV-l, and the lumbar and sacral

ganglia for HSV-2 (Fig. 46-4A). In the sensory ganglia, the virus may cause

a cytolytic infection or establish a latent, noncytolytic infection.

Sympathetic ganglia and other cell types of the central nervous system may

also serve as sites of virus latency. In the neuron, viral DNA is maintained

as an extrachromosomal plasmid (episome) with 1 to 20 copies per cell.

Current studies are examining the possibility that latent virus is

restricted by virus DNA-encoded antisense RNA molecules known as

latency-associated transcripts (LATs). Transcription of LATs is regulated by

LAT promoter elements. The LAT promoter region contains a series of

consensus elements, including a TATA box, Sp1 binding motifs, cAMP response

element and LAT promoter binding factor. Reactivation of latent infection

and an associated down regulation of the LAT promoter, often occurs after

various stress-related stimuli, e.g., heat, cold, ultraviolet light,

unrelated immune hypersensitivity reactions, pituitary or adrenal hormones,

immunosuppression, and emotional disturbance. When the latent virus is

reactivated, its genome passes anterograde in axons to the epithelium, where

productive replication takes place (Fig. 46-4B).

Varicella-Zoster Virus

After recovery from acute varicella (chickenpox), the virus establishes

latency in multiple ganglia of the human neuraxis (Fig. 46-4A). Years later,

the virus may reactivate, and the distribution of lesions in the skin

corresponds closely to areas of innervation (dermatome) from an individual

dorsal root ganglion (Fig. 46-4B). However, in immunocompromised patients,

life-threatening disseminated infections can occur. Studies suggest that the

virus is harbored in sensory ganglia (trigeminal and/or dorsal) and

satellite cells. In these cells, limited transcription may take place from

some, but not all, of the immediate early and early genes of the latent

viral genome. Thus, expression of latent varicella-zoster virus genes

appears to be different from that of HSVs. Where mainly non-polyadenylated

LATs that are antisense to immediate early transcripts are expressed and

accumulate in neuronal cells. VZV-encoded LATs are polyadenylated

transcripts of the sense direction that have a short half-life and are

detectable in non-neuronal, satellite cells and in ganglia as well. However,

there is no significant viral protein synthesis detectable from the

polyadenylated transcripts during latency. The molecular basis of latency

and reactivation of latent virus has not been fully characterized.

Human Papovaviruses

The papovaviruses (JC and BK) are widely distributed in the human

population, as evidenced by the presence of specific antibodies in 7080% of

adult sera. BK virus has been associated with hemorrhagic cystitis; however,

the site of persistence is not known. The JC virus is thought to persist in

the kidney, and is reactivated when the host immune system is impaired

(e.g., HIV infection, immunosuppressive therapy, pregnancy). JC virus is

regularly isolated from brain cells of patients with progressive multifocal

leukoencephalopathy (PML), a fatal demyelinating disease.

The mechanism of persistence for both viruses can be related to the encoded

T antigens, which are functionally similar, but antigenically distinct from

SV40 T antigen. The latent JC virus genome can randomly integrate into

cellular DNA and, when excision of viral DNA is induced, the latent genome

becomes activated, infectious virus is produced, and disease (PML) may

develop.

Prions

The subacute spongiform virus encephalopathies are a unique type of slow

virus infection caused by agents called unconventional viruses or prions

(see Ch. 71). Many lines of evidence have converged to argue that these

infectious agents are composed largely, if not entirely, of prion protein

(PrP) molecules. These proteins are encoded by wild type or mutated cellular

genes that are excluded from the particles. The human PrPs gene can be

mapped to the short arm of chromosome 20. A long incubation period (often

years to decades) with slowly rising and spreading infection precedes the

onset of clinical illness and is followed by chronic progressive disease.

The host shows no inflammatory response, no humoral or cellular immune

response, and no interferon production. Immunosuppression of the host has no

effect on pathogenesis or progression of disease. The human subacute

spongiform virus encephalopathies include kuru, Creutzfeldt-Jakob disease,

Gerstmann-Straussler-Scheinker syndrome and fatal familial insomnia.

Digestive System

Of the numerous viruses that infect the digestive system, most (the

enteroviruses and reoviruses) are considered to be acute viruses that cause

infections even though some may continue to be shed for months or even

years. Persistent infections may be caused by hepatitis viruses,

adenoviruses, and parvoviruses (Table 46-4).

Hepatitis B Virus

Persistent Hepatitis B Virus (HBV) infection may be either chronic or

latent, depending on the host cell type (see Ch. 70). Chronic hepatitis

develops in about 1015 percent of hepatitis B patients. The presence of

viral surface antigen (HBsAg) or core antigen (HbcAG) in serum serves as a

marker of persistent infection. In chronic infections, HBV productively

infects hepatocytes and maintains a low level of virus production over a

long period. Integration is not required for virus replication, but it may

be a crucial event for long-term perpetuation of the virus genome. In

addition, HBV is capable of causing latent infections (e.g., of peripheral

blood lymphocytes or bone marrow cells) in which viral gene expression is

very limited.

The factors that determine the development of chronic infection with HBV

have not been fully identified. Immune tolerance to the surface protein of

HBV appears to be one of the factors involved in the development of the

carrier state. The chronic infection is related to an inefficient T-cell

response to viral components critical for protective immunity. For example,

there is a significant deficiency of HLA-DR2 and an excess of HLA-DR7 in

patients with chronic persistent HBV infection. It appears that the HLA-DR7

molecule is unable to present the appropriate HBsAg epitope in a

configuration that can be effectively recognized by helper T cells. There is

strong epidemiological evidence of a causal relationship between persistent

HBV infection and development of hepatocellular carcinoma.

Other Hepatitis Viruses

Chronic persistent infections of hepatitis C (HCV) and type D virus (HDV) is

found throughout the world. Individuals who have antibody to hepatitis C

should be considered potentially persistently infected, and the presence of

viral RNA in infections by hepatitis C are associated with chronic

persistent or active hepatitis, cirrhosis, and hepatocellular carcinoma.

Hepatitis type D (delta agent; HDV), a defective virus that requires active

replication of coinfecting HBV for its own reproduction, may exacerbate

hepatitis B (see Ch. 70). HDV acquires an HBsAg coat for transmission. The

mechanism of this interaction is currently being studied. There is no

evidence that hepatitis A or E causes persistent infections.

Adenoviruses

Adenoviruses (AdV) typically cause acute disease of the respiratory and

gastrointestinal tracts of human beings. The high incidence of adenovirus

infections in organ transplant (kidney, bone marrow) recipients and AIDS

patients suggests that these infections most probably represent reactivation

of a latent adenovirus infection. For example, AdV can persist latently for

years in adenoids and tonsils and often are shed in the feces for many

months after the initial infection.

The mechanism and the cell type harboring the latent virus in vivo is

presently unknown. In vitro studies have shown that the strategies of C-type

AdV (types AdV2, AdV5) to evade immune recognition involve the e3 early

genomic region. Protein(s) of the e3 region alter the expression,

post-translational modification and transport of the major

histocompatibility complex (HLA class I). In addition, E3 down-regulates the

e1a gene product, the immunodominant cytotoxic T cell determinant. It is

possible that similar mechanisms operate in the host during natural

persistent infection.

Parvoviruses

The replication of the simplest DNA viruses, the parvoviruses, is dependent

on functions supplied by replicating host cells (Parvovirus genus) or by

coinfection with helper viruses, usually adenovirus (Dependovirus genus).

Both genuses have been shown to develop persistent infection in humans. For

example, parvovirus B19 infects primarily the erythroid progenitors, causing

chronic hemolytic anemia, neutropenia, and persistent arthritis mainly in

immunocompromised individuals.

The dependovirus group of parvoviruses (adeno-associated viruses; AAV) can

be isolated from fecal, ocular, or respiratory specimens and from penile and

condylomatous lesions during simultaneous adenovirus infections. The AAV

integrate into host cell DNA and replicate with it, only to be excised and

induced to replicate when the latently infected cells are superinfected with

adenoviruses. The dependoviruses are not known to be pathogenic.

Skin

Of the viruses that cause acute infections of the skin and mucous membranes,

herpesviruses (see above) and papillomaviruses (Table 46-4) are also capable

of establishing persistent infections.

Human Papillomaviruses

The ubiquity of latent papillomavirus infections is emphasized by the

frequent, often acute outbreak of warts in immunosuppressed patients and

pregnant women. HPVs specifically infect basal or germ cells of the

epidermis. The virus genome persists in episomal form, as a result of the

multiple DNA-protein and protein-protein interactions between viral and

cellular regulatory factors. In latency, viral DNA replication and

transcription are maintained at very low levels and regulated by negative

cellular factors (e.g., NF-IL6, p53, Oct-1, YY1) and low levels of early

viral proteins (E1 and E2). For example, the viral E1 replication protein

functions as an E2 co-repressor when bound to the origin of DNA replication.

Productive viral replication occurs only in terminally-differentiated skin

cells (see Fig. 66-4). Where, presumably in response to

differentiation-specific signals, viral transcription accelerates, DNA

synthesis begins and virions assemble (see Ch. 66). Persistent HPV

infections are associated with a number of skin and cervical cancers (see

Ch. 47).

_________________________________________________________________

From must-see cities to the best beaches, plan a getaway with the Spring

Travel Guide! http://special.msn.com/local/springtravel.armx