| HOME | HELP | FEEDBACK | SUBSCRIPTIONS | ARCHIVE | SEARCH | TABLE OF CONTENTS |
Regular Articles |
From the Children’s Hospital and Harvard Medical
School,*
Boston; and the New England Regional Primate
Research Center and Harvard Medical
School,
Southborough, Massachusetts
 |
Abstract |
|---|
 Top Abstract IntroductionMaterials and MethodsResultsDiscussionReferences |
|---|
4ß7 were dramatically decreased in the RLN and LP of most
SIV-infected macaques. The RLN of both naive and SIV-infected macaques
contained high numbers of CD68 + MHC-II+ macrophages and cells
expressing the co-stimulatory molecules B7-2 and CD40, as well
as IgM + MHCII+ and IgM + CD40+ B cells, indicating maintenance
of antigen presentation capacity. The LP of all three macaques
SIV-infected for 2 months contained many B7-2+ cells,
suggesting increased activation of antigen-presenting cells. LP of
SIV-infected rectal mucosa contained increased numbers of IgM+
cells, confirming previous observations in small intestine and
colon. The data suggest that antigen-presentation capacity is
maintained in inductive sites of SIV-infected rectal mucosa,
but immune effector functions may be altered.
|
Introduction |
|---|
|
TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
|---|
The rectal mucosa is of particular importance in HIV/SIV infection and transmission for several reasons. It is rich in lymphoid aggregates and follicles which have been shown to be sites of viral replication in HIV-infected patients.4 Viral production in the rectal mucosa has been implicated in transmission of HIV from infected hosts to uninfected individuals.14 The rectal mucosa offers a relatively convenient site for sampling of the GI mucosa in humans. In addition, the rectal mucosa is a site of initial HIV/SIV entry.7,15,16 Administration of antigens via the rectum of humans results in local and systemic immune responses,17,18 making the rectal mucosa an important candidate route for delivery of HIV/SIV vaccines. The cell populations responsible for induction of local immune responses in the organized lymphoid tissues of the small intestine (ie, the Peyer’s patches) have been studied in some detail,19,20 but much less is known about the lymphoid tissues of the rectum.
We therefore undertook an immunocytochemical study of the rectal mucosa in normal and SIV-infected rhesus macaques to investigate possible alterations in the cellpopulations responsible for mucosal immune function. In the intestinal mucosa, the inductive and effector arms of the immune system are anatomically distinct. Inductive sites consist of organized lymphoid tissue, seen in the rectum as isolated rectal lymphoid nodules (RLN), whereas effector sites are represented by lymphocytes scattered diffusely throughout the lamina propria (LP) and within the epithelium. In this study, the RLN and LP were examined separately, because the cellular compositions of the two compartments are distinct and thus the effects of SIV infection may differ. For example, in the rectal mucosa of HIV-infected humans, depletion of CD4+ lymphocytes is more severe in the LP than in the RLN.21 HIV/SIV infection could nevertheless interfere with the induction of immune responses in the RLN by affecting the processing and presentation of incoming foreign antigens and pathogens, depleting T cell help for generation of antigen-specific B cells and cytotoxic T lymphocytes (CTLs), and impairing cytokine production for isotype switch to IgA. In the LP, infection could disrupt other mucosal protective functions. Indeed, others have observed altered morphology of subepithelial macrophages in SIV-infected monkey colon5,6 and a reduction in LP IgA-producing cells in both HIV-infected humans and SIV-infected macaques.21-23
To examine in more detail the effects of SIV infection on both
inductive and effector sites in the rectal mucosa, cells with
antigen-presentation capacity in both RLN and LP were identified by
visualizing MHC-II and the co-stimulatory molecules CD40 and B7-2
(CD86). Possible alterations in mucosal homing/trafficking of cells to
both compartments were evaluated by immunocytochemical identification
of cells expressing the mucosal homing receptor 4ß7 and the
peripheral lymph node homing receptor L-selectin. In addition, possible
alterations in B cell populations were analyzed with regard to
expression of molecules associated with antigen presentation (MHC-II
and CD40), differentiation state (CD20), and expression of
immunoglobulin isotypes.
|
Materials and Methods |
|---|
|
TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
|---|
Rectal and distal colonic tissues (defined here as 3 to 10 cm and
10 to 15 cm from the anal verge, respectively) were obtained at
necropsy from five naive, SIV-uninfected macaques, three short-term (2
months) SIV-infected macaques, and eight long-term (5 to 21 months)
SIV-infected macaques. Although most of the sections from each group
were from the rectum some were from the adjacent distal colon, a region
in which the mucosa is histologically identical to the rectum; thus,
for brevity all of the sections used in this study are referred to as
rectal tissue. The three short-term SIV-infected macaques were
inoculated intravenously with SIVmac239 50 days before sacrifice. The
eight long-term SIV-infected rhesus macaques were inoculated
intravenously (or in one case, vaginally) with SIVmac251 or SIVmac239 5
to 21 months before sacrifice. Table 1
shows designated animal numbers, numbers of CD4+
T cells in peripheral blood, and percentages of mucosal
CD4+ T cells measured by flow cytometric analysis
of mucosal T cell populations obtained from other intestinal regions as
part of a previous study.11
All of the SIV-infected
animals in this study, with the exception of animal no. A97-254, had
opportunistic infections of the GI tract as judged by microbial
culture, histopathology, and/or clinical symptoms.
|
The reagents used in this study and their sources are shown in
Table 2
. Immediately after sacrifice,
rectal and colonic tissues were dissected, embedded in optimum cold
temperature medium (OCT; Miles Inc., Elkhart, IN), frozen in
2-methylbutane (J. T. Baker, Phillipsburg, NJ), chilled by dry
ice, and kept at -80°C until sectioned. Other tissue samples were
fixed in 4% formaldehyde and embedded in paraffin using standard
procedures. Staining with all antibodies (with the exception of
anti-S100 and HAM-56) was performed using 5-µm cryostat sections
mounted on Superfrost Plus glass slides (Fisher Scientific, Pittsburgh,
PA), dried at room temperature for 4 hours to overnight, and kept at
-80°C until use. Before immunofluorescent staining the slides were
brought to room temperature and immediately fixed with 100% acetone
for 10 minutes at room temperature. The anti-S-100 antibody was applied
to fixed, paraffin-embedded sections. The sections were washed three
times, 5 minutes each in phosphate-buffered saline (PBS), and blocked
in PBS containing 10% normal serum of the species in which the
secondary reagent was raised. Primary reagents were applied to sections
and incubated for 45 minutes at room temperature or overnight at 4°C.
The sections were washed three times, 5 minutes each in PBS containing
0.05% Tween (PBS/Tween), and secondary reagents were applied for 45
minutes at room temperature. The sections were again washed three
times, 5 minutes each in PBS/Tween and 5 minutes in PBS. Coverslips
were mounted with Gel/Mount (Biomeda Corp, Foster City, CA) and slides
were kept in the dark at room temperature until studied and
photographed. Staining was repeated on at least two slides for each
animal, with sections at least 30 µm apart. The intensity of
fluorescent staining was generally similar on all sections analyzed,
and background fluorescence was low.
|
footnotes. Flow Cytometry
The absolute numbers of CD4+ cells in peripheral blood mononuclear cells and percentage of intestinal CD4+ T cells was determined by flow cytometry on single-cell suspensions prepared from intestinal tissues as previously described.24 Briefly, pieces of jejunum, ileum, and/or colon were removed, washed in PBS, and cut into small pieces. The intestinal pieces were treated sequentially with magnesium and calcium-free Hanks’ balanced salt solution containing ethylenediaminetetraacetic acid to remove epithelial and intraepithelial cells, and then with RPMI containing 5% fetal calf serum, L-glutamine, streptomycin, and collagenase (type II; Sigma Chemical Co., St. Louis, MO) to release LP cells. The cells were separated on a Percoll density gradient, washed, and counted. Cell suspensions were then stained with an excess of phycoerythrin-conjugated anti-human CD4 monoclonal antibody (OKT4; Ortho, Raritan. NJ) for 30 minutes at 4°C, washed in PBS, and fixed overnight in 2% paraformaldehyde. Cells were analyzed using a FACS Scan flow cytometer and Cell Quest software (Becton Dickinson, Mountain View, CA). Percentages of intestinal CD4 cells were determined by gating through lymphocytes using a bivariate dot plot display of forward versus side scatter as previously described.24
Localization of SIV-Infected Cells by in Situ Hybridization and Immunohistochemistry
To identify cells that harbored viral mRNA, nonradioactive in situ hybridization was combined with immunohistochemistry on formalin-fixed, paraffin-embedded sections from rectum and distal colon as previously described.11 Briefly, a DNA probe corresponding to the entire SIVmac239 genome was labeled with digoxigenin-11-dUTP by random priming (Boehringer Mannheim, Indianapolis, IN) and hybridized onto paraffin-embedded sections overnight. Labeled cells were visualized using horseradish peroxidase-conjugated sheep anti-digoxigenin antibodies and diaminobenzidine plus nickel cobalt to give a black precipitate. In double-label experiments to determine whether cells of monocyte/macrophage lineage were infected, this was followed by immunostaining with HAM-56 using horseradish peroxidase-conjugated secondary antibody and development using diaminobenzidine alone, resulting in an orange/brown precipitate. Other paraffin sections stained with hematoxylin and eosin (H&E) were used for histological analysis of rectal mucosal tissue.
|
Results |
|---|
|
TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
|---|
RLNs were present at the recto-anal junction and at frequent intervals in the rectal and distal colonic tissues examined. The majority of RLN were located in the submucosa, but because serial sections were not examined it is possible that some of these extended into the mucosa as previously described in humans.25 The association of mucosal nodules with follicle-associated epithelium containing M cells was seen in only a few of the sections examined. The histological organization of the RLN in macaques was similar to that reported for organized mucosal lymphoid tissues in the human colon.26
Changes in the Distribution of CD4+ T Cells in Rectal Mucosa of SIV-Infected Macaques
Flow cytometry of single-cell suspensions prepared from small and
large intestines of intravenously SIV-inoculated rhesus macaques showed
that numbers of CD4+ cells were dramatically
reduced in the intestinal mucosa at early times after
infection,2,10-13
but this decrease was less dramatic in
the Peyer’s patches which contain both organized and diffuse lymphoid
tissues.11
FACS analysis of mucosal tissues from the
monkeys in this study confirmed previous reports, showing a dramatic
decrease in mucosal CD4+ cells (Table 1)
. To
separately evaluate the organized and diffuse lymphoid tissue of the
rectum, we directly visualized CD4+ cells in RLN
and LP of SIV-inoculated and naive macaques by immunofluorescent
staining. As expected from earlier reports of the small intestine and
colon, numbers of CD4+ cells were much reduced in
the rectal LP of SIV-infected macaques (data not shown). However, many
CD4+ cells were present in the RLN of
SIV-infected macaques even in monkeys at late stages of SIV infection
and AIDS. The fact that organized lymphoid tissues of the rectal mucosa
of these SIV-infected macaques contained CD4+
target cells, confirms previous observations in the small intestinal
mucosa of SIV-infected macaques11
and the rectal mucosa of
HIV-infected humans.21
In situ hybridization showed that in all specimens examined
ranging from 2 months postinfection to those with terminal AIDS, the
majority of SIV-containing cells were in the RLN and fewer were in the
LP. This is consistent with earlier findings in small and large
intestines of macaques infected for 3 to 17 months,5
and
in the upper GI tract at 2 months postinfection.11
In situ hybridization combined with immunohistochemical
staining with HAM-56, a marker for macrophage lineage cells, showed
that some (but not all) of the SIV-infected cells in both RLN and LP
were macrophages (Figure 1)
. Whether the
numbers of SIV-infected mucosal macrophages was enhanced by
opportunistic GI infections in these animals, as previously observed in
esophageal mucosa,27
could not be determined because 10 of
the 11 infected animals harbored such infections. In any case, these
results confirmed that rectal mucosal T cells and macrophages, both of
which express HIV/SIV co-receptors28
may serve as a
reservoir of SIV in the rectum even after LP CD4+
T cells are depleted.
|
4ß7 in
SIV-Infected Macaques
Lymphocytes migrate selectively into intestinal mucosal lymphoid
tissues on the basis of the surface expression of 4ß7 which
interacts with the mucosal addressin MAdCAM-1 expressed primarily on
mucosal endothelial cells. Although the homing receptor L-selectin
(CD62L) may also be expressed by some mucosal lymphocytes, it is
generally considered a homing receptor for systemic lymphoid
tissues.29
Because cell trafficking and the presence of
mucosa-specific lymphocytes may be important in the pathogenesis of
HIV/SIV and in the ability of infected animals to mount mucosal immune
responses, we studied the distribution of 4ß7+ and L-selectin+
cells in the RLN and LP of SIV-infected and naive macaques. In naive
macaques 4ß7+ cells were present in high numbers in RLN and were
also numerous in the LP (Figure 2a
, Table 3
). In contrast, the majority of
long-term SIV-infected macaques had few 4ß7+ cells in either RLN
or LP (Figure 2b
and Table 3
). In RLN of most of the naive and infected
macaques there were few or no L-selectin+ cells, as expected. Although
four out of 11 SIV-infected macaques had relatively high numbers of
L-selectin+ cells in RLN, there were wide variations among individuals
and no consistent pattern emerged (Table 3)
. In the LP of naive
macaques, low numbers of L-selectin+ cells were consistently present
(Figure 3c)
. However, in the LP of the
three macaques infected for 2 months the numbers of L-selectin+ cells
in LP were high, and L-selectin+ cells were also elevated in five of
the eight animals infected for longer times (Figure 3d
and Table 3
).
These findings suggest that in SIV-infected macaques, mucosal
trafficking of lymphocytes may be altered or mucosally directed
4ß7+ cells may fail to survive in the rectal mucosa.
|
|
|
In the normal intestinal mucosa, cells capable of presenting antigens via the MHC Class II pathway are particularly abundant in organized inductive sites but are also present in the LP. To confirm their distribution in the normal macaque rectum and to evaluate possible changes in SIV-infected animals, we began by visualizing the MHC II molecule HLA-DR, the macrophage lineage marker CD68, and the putative dendritic cell markers CD1a (a marker of Langerhans cells in stratified epithelia) and S100, an actin-associated protein enriched in dendritic cells. In RLN of naive macaques, we found CD68+HLA-DR+ macrophages scattered throughout the nodules and in the LP, CD68+HLA-DR+ cells were abundant, particularly below the surface epithelium (data not shown). Similar cell distributions were observed in sections stained with a mouse anti-human CD11b reagent. No CD1a+ cells were found in naive macaque rectal mucosa in agreement with a previous report,30 although using the same reagent we could readily detect CD1a + dendritic cells in frozen sections of tonsil (data not shown). Relatively few S100+ cells were observed in LP or RLN of naive macaques and in RLN, most of the S100+ cells were located at the periphery of the lymphoid nodules. We could not detect any alterations in the numbers or distribution of cells expressing any of these markers in SIV-infected rectal mucosa. These findings confirm the distribution of macrophage lineage cells observed by others in SIV-infected and uninfected macaque colonic mucosa.5
We then documented the distribution of cells expressing the
co-stimulatory molecules B7-2 (CD86), and CD40. In naive macaques, the
RLN contained high numbers of B7-2+ cells scattered throughout the
nodules except in areas that appeared to be germinal centers. This
distribution resembled that of CD68+ macrophages. There were also many
CD40+ cells scattered throughout the RLN and a few of these, located at
the periphery of the nodules, were intensely stained and had a
dendritic morphology. In SIV-infected macaques, we detected no
alterations in numbers and localization of B7-2+ or CD40+ cells in RLN
(Figure 4a
and Table 4
). These finding confirm that the
lymphoid nodules of the rectal mucosa are potential sites of
antigen-presentation activity and that this immunophenotype is
maintained in RLN, even in long-term SIV-infected macaques. In the LP,
the putative effector site, we detected few or no B7-2+ cells in four
of the five naive macaques (Figure 3a
and Table 4
). In contrast, many
B7-2+ cells were present in the LP of all three short-term SIV-infected
macaques and four of eight long-term SIV-infected macaques (Figure 3b
and Table 4
). We did not detect CD40+ cells in the LP of any naive
macaques and detected CD40+ cells in the LP of only three of 11
SIV-infected macaques (Table 4)
. These data suggest that the LP of
SIV-infected macaques contains cells with the potential to function as
antigen-presenting cells, despite the marked depletion of
CD4+ T helper cells.
|
|
and Table 5
). The IgM + MHCII+ cells were
generally located outside apparent germinal center areas, whereas the
IgM + CD40+ cells were found within these areas. These data suggest
that some RLN B cells are potentially capable of functioning as antigen
presenting cells (APC). Although IgM+ cells were present in the LP of
naive macaques and were abundant in LP of SIV-infected macaques, none
of them expressed MHCII+ or CD40+ (data not shown).
|
Decreases in IgA+ cells and increases in IgM+ cells were
previously reported in the LP of small intestine and colon of
SIV-infected macaques,23
but the phenotypes of B cells in
the rectal mucosa had not been examined. Rectal B cells expressing
immunoglobulin isotypes were visualized by double immunofluorescent
staining of IgM with IgA or IgG. The RLN of both naive and SIV-infected
macaques contained mainly IgM+ cells and few or no IgA+ (Table 5)
or
IgG+ (data not shown) cells, as others have observed (J. Mestecky,
personal communication). The LP of SIV-infected macaques showed an
increase in the numbers of IgM+ cells and a decrease in IgA+ cells when
compared to the LP of naive macaques (data not shown), consistent with
previous reports.23
By double-immunofluorescent staining
to visualize IgM and secretory component (SC), we detected similar
levels of SC on crypt epithelial cells and co-localization of SC and
IgM within epithelial cells and in the lumen of both naive and
SIV-infected macaques, as expected (data not shown).
The increase in IgM+ B cells in SIV-infected LP raised the
possibility that some of these cells might not only have failed to
switch to the IgA isotype, but also failed to terminally differentiate
into plasma cells. To determine what proportion of the IgM+ B cells in
rectal LP were terminally differentiated, we performed
double-immunofluorescent staining of IgM with CD20 (a B-cell
differentiation marker expressed on B cells but not plasma cells) and
Ki67 (a cell proliferation marker). In RLN of both naive and
SIV-infected macaques, we found high numbers of IgM + CD20+ cells
throughout the nodules as expected, indicating that the majority of B
cells in these inductive sites were not plasma cells (Table 5)
. In RLN,
there were relatively few proliferating IgM + Ki67+ cells in both naive
and SIV-infected macaques and these were confined mostly to the
germinal centers as expected. In the LP of both SIV-infected and naive
macaques, none of the IgM+ cells co-expressed either CD20 or Ki67
(datanot shown), confirming that all of these cells were terminally
differentiated plasma cells.
|
Discussion |
|---|
|
TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
|---|
4ß7 mucosal homing receptor were depleted. In contrast, the
cellular composition of organized mucosal lymphoid nodules showed fewer
alterations; in particular, CD4+ T cells and
activated antigen-presenting cells persisted in these inductive sites
despite the presence of many SIV-infected cells.
There is abundant evidence that organized mucosal lymphoid tissues play
a major role in antigen sampling and generation of lymphocytes
including specific IgA effector B cells and T cells. This involves
active lymphocyte proliferation, local production of certain cytokines,
and continuous cellular trafficking.19,20,31,32
Most of
the available information about the cellular composition and function
of mucosal lymphoid nodules has been obtained using macroscopically
visible Peyer’s patches of the small intestine, where lymphoid
follicles are aggregated. The structure and function of solitary
lymphoid nodules that are numerous in the lower colon and
rectum26
is generally assumed to be similar to those of
Peyer’s patches, although detailed studies have not been done. In
normal intestine, antigens and pathogens are delivered by M cells in
the follicle-associated epithelium from the lumen to subepithelial
antigen-presenting cells, and hence into organized lymphoid
follicles.33,34
The organized lymphoid nodules of Peyer’s
patches generally have a central B cell-rich region (which may include
a germinal center) containing a network of macrophages and dendritic
cells where antigen presentation, B cell expansion, and isotype switch
is thought to occur.20,31,32
Adjacent to the B cell center
are CD4+ T cell-rich areas where monocytes and
naive and memory lymphocytes enter the mucosa via high endothelial
venules, directed by their 4ß7 mucosal homing receptors. Our
findings indicate that the lymphoid nodules of normal macaque rectum,
like those of Peyer’s patches, are sites of antigen presentation as
evidenced by expression of MHC-II and possibly B7-2 by macrophages and
MHC-II and CD40 by IgM+ B cells. Moreover, B cell
proliferation occurs in rectal nodules, as indicated by the presence of
IgM + /Ki67+ and IgM + CD20+ cells. We confirmed that B cells in RLN of
both naive and SIV-infected macaques were dominated by IgM+ cells, in
contrast to the IgA+ cells observed in Peyer’s patches of other
mammalian species including humans.20,31,32
At the postinfection times studied here (2 months or more), most of the
SIV-infected cells in the rectal mucosa appeared to be located in the
lymphoid nodules, as others have observed.5,6,11
Nevertheless, we found immunophenotypic evidence of high antigen
presentation capacity in these inductive sites. The numbers of CD68 +
MHCII+, IgM + MHCII+, CD40+, and B7-2+ cells in RLNs of naive and
SIV-infected rhesus macaques were comparable, and the presence of
CD4+ cells in mucosal nodules of SIV-infected
macaques indicated that some T cell help was maintained in these
inductive sites. The only clear change detected in the nodules was a
decrease in the numbers of cells expressing the mucosal homing receptor
4ß7.
A similar shift was observed in the LP of SIV-infected animals, where
4ß7+ cells were depleted and L-selectin+ cells were generally more
numerous than in naive controls. This observation is difficult to
interpret because almost all of the SIV-infected macaques in our study
had signs of gastrointestinal inflammation and/or documented
opportunistic mucosal infections. Because inflammatory and infectious
diseases of the GI tract are generally accompanied by an influx of
4ß7+ cells into the LP,35,36
we expected an increase
in the number of 4ß7+ cells in the LP of SIV-infected macaques.
The fact that we observed a decrease suggests that the loss of
4ß7+ cells in the rectal mucosa of SIV-infected macaques may be
specifically associated with SIV infection. CD4+
T cells are depleted early in the intestinal LP,10-13
and
it may be argued that the reduction in the number of 4ß7+ cells
simply reflects the loss of CD4+ T cells. On the
other hand CD8+ T cells, whose numbers are increased after SIV/HIV
infection11
as well as B cells, plasma cells, and
macrophages, can also express 4ß729,36-38
and
similar numbers of total CD3+ T cells were observed in the intestinal
mucosa of SIV-infected and naive macaques in previous
studies.11
It remains to be determined whether the
SIV-associated loss of mucosal 4ß7+ cells reflects altered mucosal
trafficking as suggested by others15
or selective loss of
mucosally directed cells.
In naive macaques, the expression of the co-stimulatory molecules CD40 and B7-2 was primarily confined to the RLN and not the LP, consistent with the hypothesis that the organized lymphoid tissues are the principal inductive sites of the rectum. In SIV-infected macaques, however, numbers of B7-2+ macrophages were increased in the LP. Although this observation suggests that antigen-presentation activity was elevated in SIV-infected rectal mucosa, it cannot be directly attributed to SIV. Antigenic stimulation from the opportunistic mucosal infections in these animals could have affected the numbers and activity of these cells, as observed by others in esophageal mucosa of SIV-infected macaques.27
In conclusion, our observations show that the organized lymphoid
tissues of the rectal mucosa of SIV-infected macaques retain the
immunophenotypic characteristics associated with high
antigen-presentation capacity. In the LP, however, the loss of
4ß7+ cells, along with loss of CD4+ T cells
and changes in the isotype distribution of secreted antibodies, suggest
alterations in immune effector functions. Elucidation of the
significance of these changes will require further studies.
|
Acknowledgements |
|---|
|
Footnotes |
|---|
Supported by National Institutes of Health Integrated Preclinical/Clinical AIDS Vaccine Development Grant A13565; National Institutes of Health Research Grants AI34757, AI38559, AI25328, and DK50550; and National Institutes of Health Grant DK34854 to the Harvard Digestive Diseases Center.
Accepted for publication April 27, 2000.
|
References |
|---|
|
TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
|---|
4ß7 by circulating CD4+ cells with memory for intestinal rotavirus. J Clin Invest 1997, 100:1204-1208[Medline]
4ß7 and Eß7 integrins on thymocytes, intestinal epithelial lymphocytes and peripheral lymphocytes. Eur J Immunol 1996, 26:897-905[Medline]
This article has been cited by other articles:
 |
|
 |
|
  S. Mehandru, M. A. Poles, K. Tenner-Racz, A. Horowitz, A. Hurley, C. Hogan, D. Boden, P. Racz, and M. Markowitz Primary HIV-1 Infection Is Associated with Preferential Depletion of CD4+ T Lymphocytes from Effector Sites in the Gastrointestinal Tract J. Exp. Med., September 20, 2004; 200(6): 761 - 770. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 B. L. Shacklett, C. A. Cox, J. K. Sandberg, N. H. Stollman, M. A. Jacobson, and D. F. Nixon Trafficking of Human Immunodeficiency Virus Type 1-Specific CD8+ T Cells to Gut-Associated Lymphoid Tissue during Chronic Infection J. Virol., May 15, 2003; 77(10): 5621 - 5631. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 R. W. Scamurra, D. B. Nelson, X. M. Lin, D. J. Miller, G. J. Silverman, T. Kappel, J. R. Thurn, E. Lorenz, A. Kulkarni-Narla, and E. N. Janoff Mucosal Plasma Cell Repertoire During HIV-1 Infection J. Immunol., October 1, 2002; 169(7): 4008 - 4016. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 R. Krzysiek, A. Rudent, L. Bouchet-Delbos, A. Foussat, C. Boutillon, A. Portier, D. Ingrand, D. Sereni, P. Galanaud, L. Grangeot-Keros, et al. Preferential and persistent depletion of CCR5+ T-helper lymphocytes with nonlymphoid homing potential despite early treatment of primary HIV infection Blood, November 15, 2001; 98(10): 3169 - 3171. [Abstract] [Full Text] [PDF]
|
|
| |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| HOME | HELP | FEEDBACK | SUBSCRIPTIONS | ARCHIVE | SEARCH | TABLE OF CONTENTS |
