2 MMR dendritic cells, intestines, measles, DE Griffin
binstoct at essex.UCHSC.edu
Tue Apr 14 10:04:01 EST 1998
Date: Thu, 2 Apr 1998 13:47:50 -0700 (MST)
From: Teresa Binstock <binstoct at essex.UCHSC.edu>
To: AUTISM at maelstrom.stjohns.edu
Subject: 2 dendritic cells, intestines, measles...
Here are some of the Diane E Griffin et al citations describing
explorations of altered immunity due to wild-type measles and/or due to
vaccine-type measles. The work of Dr. Griffin and her colleagues at Johns
Hopkins nicely augments (i) the measles/dendritic-cells/intestines
information cited in the March 19, 1998, article in Nature, and (ii) the
initial measles/intestines findings reported by Andy J. Wakefield and
colleagues (Lancet, Feb 28, 1998). Cite 7 is particularly relevant.
<1> Hussey GD et al. The effect of Edmonston-Zagreb and Schwarz measles
vaccines on immune response in infants.
Journal of Infectious Diseases. 173(6):1320-6, 1996 Jun.
The effects of measles immunization on immune responses in infants and the
roles of vaccine strain and age of immunization are not known.
Eighty-eight children were immunized at 6 or 9 months of age with the
Edmonston-Zagreb (EZ) or Schwarz (SW6, SW9) strain of measles vaccine.
Children were studied before and 2 weeks and 3 months after immunization.
Seroconversion was similar, but geometric mean neutralizing titers at 3
months differed by vaccine group: SW9, 1367 mIU/mL; SW6, 982; and EZ, 303
(P = .003). Mitogen-induced lymphoproliferation was decreased at 2 weeks
in the SW9 group and at 3 months in all groups and was negatively
correlated with measles antibody level at 3 months (r = -.387, P = .003).
CD8 T cells, soluble CD8, neopterin, and beta2-microglobulin were
increased at 2 weeks in the SW9 group, and soluble CD8 and
beta2-microglobulin remained elevated at 3 months. Therefore, measles
immunization resulted in suppression of lymphoproliferation, which was
most evident in infants with the highest antibody responses and most
<2> Auwaerter PG et al. Measles virus infection of thymic epithelium in
the SCID-hu mouse leads to thymocyte apoptosis.
Journal of Virology. 70(6):3734-40, 1996 Jun.
Mortality from measles is caused mostly by secondary infections associated
with the depression of cellular immunity. The mechanism of immune
suppression and the role of virus strain differences on the immune system
are incompletely understood. SCID-hu mice were used to determine the
effects of virulent, wild-type (Chicago-1) and avirulent, vaccine
(Moraten) strains of measles virus (MV) on the human thymus in vivo.
Chicago-1 replicated rapidly, with a 100-fold decrease in numbers of
thymocytes, whereas Moraten replicated slowly, without significant
thymocyte death. Productive MV infection occurred not in thymocytes but in
thymic epithelial and myelomonocytic cells. Wild-type MV infection of
thymic stromata leads to induction of thymocyte apoptosis and may
contribute to a long-term alteration of immune responses. The extent of
thymic disruption reflects the virulence of the virus, and therefore the
SCID-hu mouse may serve as the first small animal model for the study of
<3> Auwaerter PG et al. Changes within T cell receptor V beta subsets in
infants following measles vaccination.
Clinical Immunology & Immunopathology. 79(2):163-70, 1996 May.
Measles produces immune suppression which contributes to an increased
susceptibility to other infections. Recently, high titered measles
vaccines have been linked to increased long-term mortality among some
female recipients. Because the mechanisms by which wild-type or attenuated
live-vaccine strains of measles virus alter subsequent immune responses
are not fully understood, this prompted an examination of the changes
within the peripheral blood T cell receptor V beta repertoire following
measles immunization. Twenty-four 6- and 9-month-old infants were studied
at 2 weeks and 3 months following immunization by semiquantitative reverse
transcription-polymerase chain reaction. There was a significant increase
in V beta 2 expression (P less than 0.05), and a decrease in the V beta 4
subset (P less than 0.03) 2 weeks following vaccination with subsequent
return to baselines at 3 months in vaccine recipients who seroconverted.
These data suggest that measles virus may affect immune responses in part
by altering the T cell receptor repertoire.
<4> Esolen LM et al. Apoptosis as a cause of death in measles
Journal of Virology. 69(6):3955-8, 1995 Jun.
To determine the mechanism of measles virus-induced cell death, we studied
the infection of Vero cells and monocytic cell lines with wild-type
(Chicago-1) and vaccine (Edmonston) strains of measles virus. DNA
fragmentation indicative of apoptosis was apparent by flow cytometry,
agarose gel electrophoresis, and electron microscopy. Within syncytia, DNA
strand breaks were demonstrated by end labeling with terminal transferase
and then by visualization.
<5> Ward BJ. Griffin DE.
Changes in cytokine production after measles virus vaccination:
predominant production of IL-4 suggests induction of a Th2 response.
Clinical Immunology & Immunopathology. 67(2):171-7, 1993 May.
Immunization with live measles virus vaccine produces transient depression
of delayed-type hypersensitivity (DTH) skin test responses and
mitogen-induced lymphoproliferation irrespective of the serostatus of the
recipient of the vaccine. To investigate this immune suppression further
we studied peripheral blood mononuclear cells (PBMC) from adults before (N
= 17) and at various times after (N = 34) immunization with measles virus
vaccine. PHA-induced lymphoproliferation was decreased after vaccine and
this was partly reversed by supplementation with rIL-2. There was no
change in the proportion of PBMC that were CD4+ T cells, CD8+ T cells, NK
cells, or B cells as analyzed by flow cytometry. Supernatant fluids were
collected from PBMC after 72 hr in culture. Analysis for cytokines after
vaccination showed spontaneous production of high levels of IL-4
(vaccinees 99 +/- 23; controls 5.6 +/- 5.6 ng/ml, P = 0.031) and TNF alpha
(vaccinees 140 +/- 45; controls 42 +/- 14 pg/ml, P = 0.072) accompanied by
low levels of IFN-gamma (vaccinees 1.3 +/- 0.6; controls 14.3 +/- 10.1
U/ml), IL-1 alpha (vaccinees 111 +/- 22; controls 442 +/- 107 pg/ml, P =
0.0001), and PGE2 (vaccinees 75 +/- 39; controls 300 +/- 72 pg/ml, P =
0.048). Increased amounts of IL-4 were also produced after stimulation
with PHA (vaccinees 140 +/- 25; controls 40 +/- 40 ng/ml, P = 0.013) while
levels of IFN-gamma and soluble IL-2 receptor were similar to controls and
levels of IL-1 alpha (vaccinees 443 +/- 67; controls 792 +/- 118 pg/ml, P
= 0.026) remained low. Addition of rIL-2 had little effect on these
cytokine levels. These data suggest that Th2 cells producing IL-4 are
preferentially activated by measures vaccine and may contribute to the
immunologic abnormalities associated with immunization for measles and
possibly other viral infections.
<6> Wu VH et al. Measles virus-specific cellular immunity in patients
with vaccine failure.
Journal of Clinical Microbiology. 31(1):118-22, 1993 Jan.
The cytotoxic T-lymphocyte (CTL) response to measles virus (MV) was
studied in blood samples from 13 acute- and early convalescent-phase
patients with measles infection despite previous vaccination with the
live-MV vaccine. MV CTL responses were also measured in six healthy peer
controls who had live-MV vaccination during childhood and in five healthy
adults who had a remote history of natural measles. All patients recovered
from illness without complication. Acute MV infection was diagnosed on the
basis of the Centers for Disease Control criteria and by measuring
MV-specific immunoglobulin G (IgG) and IgM antibodies. Elevated IgG titers
occurred in 80% of the patients at 1 to 2 weeks and in 100% at 4 weeks
postinfection. IgM antibodies were detectable in all patient tested and
were elevated in 60% of the patients at 1 to 2 weeks postinfection. The
MV-specific CTL response was enhanced in 10 of the 13 patients tested,
with a mean maximal lysis of 48.5% +/- 13.3%, compared with that of
healthy peer controls who had had live-MV vaccinations during childhood
(mean lysis, 14.6% +/- 12.9%; n = 6) and healthy adults with a remote
history of natural measles (mean, 30.8% +/- 12.2%; n = 5). Three patients
had low MV CTL levels at two time points following measles, with a mean
lysis of 12% +/- 1.7%. It is concluded that while there is no evidence for
a deficiency in the generation of cellular immunity to MV in the majority
of patients with MV vaccine failure, a small number of individuals may
fail to develop an enhanced T-cell response following infection.
<7> Johnson RT et al. Measles encephalomyelitis--clinical and immunologic
New England Journal of Medicine. 310(3):137-41, 1984 Jan 19.
We studied 19 patients with postinfectious encephalomyelitis complicating
natural measles-virus infections, and our results support the hypothesis
that this demyelinating disease has a pathogenesis similar to that of
experimental allergic encephalomyelitis. Early myelin destruction was
demonstrated by the presence of myelin basic protein in cerebrospinal
fluid, and lymphocyte proliferative responses to myelin basic protein were
found in 8 of 17 patients tested. A lack of intrathecal synthesis of
antibody against measles virus suggests that measles encephalomyelitis may
not be dependent on virus replication within the central nervous system.
Similar lymphoproliferative responses to myelin basic protein of
lymphocytes from single patients with encephalomyelitis after rabies
vaccine or after varicella or rubella virus infections suggest a common
immune-mediated pathogenesis for the perivenular demyelinating disease
that can follow the injection of neural tissues or infection by a variety
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