2 MMR dendritic cells, intestines, measles, DE Griffin

[Teresa Binstock]

		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
  immune activation.

<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
  MV pathogenesis.

<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
virus-infected cells.
	  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
studies.
	  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
  of viruses.