{"id":{"repo_id":"kings","oai_identifier":"oai:kclpure.kcl.ac.uk:studenttheses/c91e6203-4010-497d-8773-9b5c622a1372"},"canonical_url":"https://search.dev.ndltd.org/etd/kings/oai:kclpure.kcl.ac.uk:studenttheses/c91e6203-4010-497d-8773-9b5c622a1372","repository":{"repo_id":"kings","name":"King's College London","base_url":"https://kclpure.kcl.ac.uk/ws/oai"},"display":{"title":"The role of B cells in the amplification and in the regulation of transplant rejection.","abstract":"B cells are known to contribute to and/or influence immune response trough a
variety of mechanisms. Regulatory B cells (Bregs) have recently discovered and
their role in regulating autoimmune diseases has been demonstrated in different
murine models. In the context of transplantation B cells are generally thought to
promote graft rejection through the production of alloantibody and their capacity
to efficiently present alloantigens. However, recent clinical trials with B cell
depletion have suggested that B cells contribute to the regulation of immune
responses to grafts. In addition the evidence that renal transplant patients that
are tolerant to the graft have an expansion of B cells with a regulatory
phenotype further confirm this idea.
The hypothesis tested during this PhD is that murine regulatory B cells, defined
as transitional-2 marginal zone precursor (T2-MZP), are contributing to
transplantation tolerance. The aims of this project are: i) to investigate whether
T2-MZP can transfer transplantation tolerance; ii) to analyse whether the
expression of Galectin-1 (Gal-1), known to be a functional molecule for Tregs, is
necessary for T2-MZP to suppress; iii) to study whether an increase in T2-MZP
is observed in tolerant mice like what has been shown in tolerant transplant
patients.
The results obtained during this PhD have demonstrated that T2-MZP purified
from naïve mice were unable to regulate the immune responses to graft
antigens both in vitro and in vivo. However, their regulatory capacity was
observed when T2-MZP were purified from mice kept in the conventional (CV)
area of the animal house although IL-10 was not involved in their regulatory
4
capacity. A difference in the gut flora between mice kept in the Specificpathogen-
Free (SPF) and CV areas was observed and maybe responsible for
the differences in the T2-MZP functions. Moreover, Gal-1 was confirmed to be
expressed by B cells and T2-MZP isolated from Gal-1-/- mice kept in the CV
area lost the ability to suppress in vitro CD4+ T cell activation and to prolong
skin graft survivals, suggesting that Gal-1 has a functional role in B cell
suppressive function. One of the hypotheses was that the absence of Gal-1
influences the response of B cells to gut. Gal-1-/- B cells showed reduced IL-10
production and increased up-regulation of activation markers in response to a
variety of Toll-like receptor ligands in comparison to wild-type B cells, and
showed differences in the percentage of P38, ERK phosphorylation and NF-κB
translocation. Finally, in trying to mimic the findings with renal transplant
patients, mice were rendered tolerant to skin transplants using in vivo anti-
CD40L (MR1) and donor splenocyte transfusion (DST). The number of T2-MZP
increased in these mice and these cells were suppressive in vitro and, as
before, their regulatory capacity did not appear to correlate with IL-10
production. Once transferred in vivo T2-MZP isolated from tolerant mice, and
not animal rejecting an allograft, induced prolongation of skin transplants onto
naïve recipients.
These observations indicate that T2-MZP play a role in transplant tolerance,
they need to be “primed” either during tolerance induction protocol or by
interaction with gut flora and that Gal-1 is a functional molecule for B cells and
T2-MZP B cells.","abstract_html":"B cells are known to contribute to and/or influence immune response trough a<br/>variety of mechanisms. Regulatory B cells (Bregs) have recently discovered and<br/>their role in regulating autoimmune diseases has been demonstrated in different<br/>murine models. In the context of transplantation B cells are generally thought to<br/>promote graft rejection through the production of alloantibody and their capacity<br/>to efficiently present alloantigens. However, recent clinical trials with B cell<br/>depletion have suggested that B cells contribute to the regulation of immune<br/>responses to grafts. In addition the evidence that renal transplant patients that<br/>are tolerant to the graft have an expansion of B cells with a regulatory<br/>phenotype further confirm this idea.<br/>The hypothesis tested during this PhD is that murine regulatory B cells, defined<br/>as transitional-2 marginal zone precursor (T2-MZP), are contributing to<br/>transplantation tolerance. The aims of this project are: i) to investigate whether<br/>T2-MZP can transfer transplantation tolerance; ii) to analyse whether the<br/>expression of Galectin-1 (Gal-1), known to be a functional molecule for Tregs, is<br/>necessary for T2-MZP to suppress; iii) to study whether an increase in T2-MZP<br/>is observed in tolerant mice like what has been shown in tolerant transplant<br/>patients.<br/>The results obtained during this PhD have demonstrated that T2-MZP purified<br/>from naïve mice were unable to regulate the immune responses to graft<br/>antigens both in vitro and in vivo. However, their regulatory capacity was<br/>observed when T2-MZP were purified from mice kept in the conventional (CV)<br/>area of the animal house although IL-10 was not involved in their regulatory<br/>4<br/>capacity. A difference in the gut flora between mice kept in the Specificpathogen-<br/>Free (SPF) and CV areas was observed and maybe responsible for<br/>the differences in the T2-MZP functions. Moreover, Gal-1 was confirmed to be<br/>expressed by B cells and T2-MZP isolated from Gal-1-/- mice kept in the CV<br/>area lost the ability to suppress in vitro CD4+ T cell activation and to prolong<br/>skin graft survivals, suggesting that Gal-1 has a functional role in B cell<br/>suppressive function. One of the hypotheses was that the absence of Gal-1<br/>influences the response of B cells to gut. Gal-1-/- B cells showed reduced IL-10<br/>production and increased up-regulation of activation markers in response to a<br/>variety of Toll-like receptor ligands in comparison to wild-type B cells, and<br/>showed differences in the percentage of P38, ERK phosphorylation and NF-κB<br/>translocation. Finally, in trying to mimic the findings with renal transplant<br/>patients, mice were rendered tolerant to skin transplants using in vivo anti-<br/>CD40L (MR1) and donor splenocyte transfusion (DST). The number of T2-MZP<br/>increased in these mice and these cells were suppressive in vitro and, as<br/>before, their regulatory capacity did not appear to correlate with IL-10<br/>production. Once transferred in vivo T2-MZP isolated from tolerant mice, and<br/>not animal rejecting an allograft, induced prolongation of skin transplants onto<br/>naïve recipients.<br/>These observations indicate that T2-MZP play a role in transplant tolerance,<br/>they need to be “primed” either during tolerance induction protocol or by<br/>interaction with gut flora and that Gal-1 is a functional molecule for B cells and<br/>T2-MZP B cells.","abstract_has_math":false,"creators":["Alhabbab, Rowa"],"institution":"King's College London","degree_name":"Doctor of Philosophy","degree_level":"Doctoral Thesis","degree_discipline":null,"degree_department":null,"school":null,"contributors":[],"advisors":["Blair, Paul Anthony","Lombardi, Giovanna","Lechler, Robert Ian"],"committee_chairs":[],"committee_members":[],"year":2013,"date_issued":"2013-2-1","date_published":"2013-2-1","updated_at":"2026-07-24T02:44:31Z","subjects":[],"languages":["eng"],"rights":[],"rights_urls":[],"identifier_entries":[{"key":"dc:identifier","label":"Identifier","values":["oai:kclpure.kcl.ac.uk:studenttheses/c91e6203-4010-497d-8773-9b5c622a1372"],"render_values":[{"text":"oai:kclpure.kcl.ac.uk:studenttheses/c91e6203-4010-497d-8773-9b5c622a1372","href":null,"code":true}]}]},"links":{"outbound_url":"https://kclpure.kcl.ac.uk/portal/en/studentTheses/c91e6203-4010-497d-8773-9b5c622a1372","outbound_label":"Repository record","outbound_source":"dc:identifier"},"metadata_groups":[{"id":"people","label":"People","entries":[{"key":"dc:contributor.advisor","label":"Advisor","values":["Blair, Paul Anthony","Lombardi, Giovanna","Lechler, Robert Ian"]},{"key":"dc:creator","label":"Author","values":["Alhabbab, Rowa"]}]},{"id":"academic_context","label":"Academic Context","entries":[{"key":"dc:date","label":"Dc Date","values":["2013-2-1"]},{"key":"dc:date.issued","label":"Date","values":["2013-2-1"]},{"key":"dc:publisher.department","label":"Dc Publisher Department","values":["Immunoregulation & Immune Intervention"]},{"key":"dc:publisher.institution","label":"Dc Publisher Institution","values":["King's College London"]},{"key":"dc:relation.isreferencedby","label":"Dc Relation Isreferencedby","values":["https://kclpure.kcl.ac.uk/portal/en/studentTheses/c91e6203-4010-497d-8773-9b5c622a1372"]},{"key":"dc:type","label":"Dc Type","values":["Thesis"]},{"key":"dc:type.qualificationlevel","label":"Dc Type Qualificationlevel","values":["Doctoral Thesis"]},{"key":"dc:type.qualificationname","label":"Dc Type Qualificationname","values":["Doctor of Philosophy"]}]},{"id":"language_rights","label":"Language and Rights","entries":[{"key":"dc:language","label":"Dc Language","values":["eng"]}]},{"id":"identifiers","label":"Identifiers","entries":[{"key":"dc:identifier","label":"Identifier","values":["oai:kclpure.kcl.ac.uk:studenttheses/c91e6203-4010-497d-8773-9b5c622a1372","https://kclpure.kcl.ac.uk/portal/en/studentTheses/c91e6203-4010-497d-8773-9b5c622a1372"]},{"key":"dc:identifier.uri","label":"Identifier URI","values":["https://kclpure.kcl.ac.uk/portal/files/12371843/Studentthesis-Rowa_Alhabbab_2013.pdf"]}]},{"id":"additional","label":"Additional Metadata","entries":[{"key":"dc:description.abstract","label":"Abstract","values":["B cells are known to contribute to and/or influence immune response trough a
variety of mechanisms. Regulatory B cells (Bregs) have recently discovered and
their role in regulating autoimmune diseases has been demonstrated in different
murine models. In the context of transplantation B cells are generally thought to
promote graft rejection through the production of alloantibody and their capacity
to efficiently present alloantigens. However, recent clinical trials with B cell
depletion have suggested that B cells contribute to the regulation of immune
responses to grafts. In addition the evidence that renal transplant patients that
are tolerant to the graft have an expansion of B cells with a regulatory
phenotype further confirm this idea.
The hypothesis tested during this PhD is that murine regulatory B cells, defined
as transitional-2 marginal zone precursor (T2-MZP), are contributing to
transplantation tolerance. The aims of this project are: i) to investigate whether
T2-MZP can transfer transplantation tolerance; ii) to analyse whether the
expression of Galectin-1 (Gal-1), known to be a functional molecule for Tregs, is
necessary for T2-MZP to suppress; iii) to study whether an increase in T2-MZP
is observed in tolerant mice like what has been shown in tolerant transplant
patients.
The results obtained during this PhD have demonstrated that T2-MZP purified
from naïve mice were unable to regulate the immune responses to graft
antigens both in vitro and in vivo. However, their regulatory capacity was
observed when T2-MZP were purified from mice kept in the conventional (CV)
area of the animal house although IL-10 was not involved in their regulatory
4
capacity. A difference in the gut flora between mice kept in the Specificpathogen-
Free (SPF) and CV areas was observed and maybe responsible for
the differences in the T2-MZP functions. Moreover, Gal-1 was confirmed to be
expressed by B cells and T2-MZP isolated from Gal-1-/- mice kept in the CV
area lost the ability to suppress in vitro CD4+ T cell activation and to prolong
skin graft survivals, suggesting that Gal-1 has a functional role in B cell
suppressive function. One of the hypotheses was that the absence of Gal-1
influences the response of B cells to gut. Gal-1-/- B cells showed reduced IL-10
production and increased up-regulation of activation markers in response to a
variety of Toll-like receptor ligands in comparison to wild-type B cells, and
showed differences in the percentage of P38, ERK phosphorylation and NF-κB
translocation. Finally, in trying to mimic the findings with renal transplant
patients, mice were rendered tolerant to skin transplants using in vivo anti-
CD40L (MR1) and donor splenocyte transfusion (DST). The number of T2-MZP
increased in these mice and these cells were suppressive in vitro and, as
before, their regulatory capacity did not appear to correlate with IL-10
production. Once transferred in vivo T2-MZP isolated from tolerant mice, and
not animal rejecting an allograft, induced prolongation of skin transplants onto
naïve recipients.
These observations indicate that T2-MZP play a role in transplant tolerance,
they need to be “primed” either during tolerance induction protocol or by
interaction with gut flora and that Gal-1 is a functional molecule for B cells and
T2-MZP B cells."]},{"key":"dc:title","label":"Title","values":["The role of B cells in the amplification and in the regulation of transplant rejection."]}]}],"canonical_facts":{"dc:contributor.advisor":["Blair, Paul Anthony","Lombardi, Giovanna","Lechler, Robert Ian"],"dc:creator":["Alhabbab, Rowa"],"dc:date":["2013-2-1"],"dc:date.issued":["2013-2-1"],"dc:description.abstract":["B cells are known to contribute to and/or influence immune response trough a
variety of mechanisms. Regulatory B cells (Bregs) have recently discovered and
their role in regulating autoimmune diseases has been demonstrated in different
murine models. In the context of transplantation B cells are generally thought to
promote graft rejection through the production of alloantibody and their capacity
to efficiently present alloantigens. However, recent clinical trials with B cell
depletion have suggested that B cells contribute to the regulation of immune
responses to grafts. In addition the evidence that renal transplant patients that
are tolerant to the graft have an expansion of B cells with a regulatory
phenotype further confirm this idea.
The hypothesis tested during this PhD is that murine regulatory B cells, defined
as transitional-2 marginal zone precursor (T2-MZP), are contributing to
transplantation tolerance. The aims of this project are: i) to investigate whether
T2-MZP can transfer transplantation tolerance; ii) to analyse whether the
expression of Galectin-1 (Gal-1), known to be a functional molecule for Tregs, is
necessary for T2-MZP to suppress; iii) to study whether an increase in T2-MZP
is observed in tolerant mice like what has been shown in tolerant transplant
patients.
The results obtained during this PhD have demonstrated that T2-MZP purified
from naïve mice were unable to regulate the immune responses to graft
antigens both in vitro and in vivo. However, their regulatory capacity was
observed when T2-MZP were purified from mice kept in the conventional (CV)
area of the animal house although IL-10 was not involved in their regulatory
4
capacity. A difference in the gut flora between mice kept in the Specificpathogen-
Free (SPF) and CV areas was observed and maybe responsible for
the differences in the T2-MZP functions. Moreover, Gal-1 was confirmed to be
expressed by B cells and T2-MZP isolated from Gal-1-/- mice kept in the CV
area lost the ability to suppress in vitro CD4+ T cell activation and to prolong
skin graft survivals, suggesting that Gal-1 has a functional role in B cell
suppressive function. One of the hypotheses was that the absence of Gal-1
influences the response of B cells to gut. Gal-1-/- B cells showed reduced IL-10
production and increased up-regulation of activation markers in response to a
variety of Toll-like receptor ligands in comparison to wild-type B cells, and
showed differences in the percentage of P38, ERK phosphorylation and NF-κB
translocation. Finally, in trying to mimic the findings with renal transplant
patients, mice were rendered tolerant to skin transplants using in vivo anti-
CD40L (MR1) and donor splenocyte transfusion (DST). The number of T2-MZP
increased in these mice and these cells were suppressive in vitro and, as
before, their regulatory capacity did not appear to correlate with IL-10
production. Once transferred in vivo T2-MZP isolated from tolerant mice, and
not animal rejecting an allograft, induced prolongation of skin transplants onto
naïve recipients.
These observations indicate that T2-MZP play a role in transplant tolerance,
they need to be “primed” either during tolerance induction protocol or by
interaction with gut flora and that Gal-1 is a functional molecule for B cells and
T2-MZP B cells."],"dc:identifier":["oai:kclpure.kcl.ac.uk:studenttheses/c91e6203-4010-497d-8773-9b5c622a1372","https://kclpure.kcl.ac.uk/portal/en/studentTheses/c91e6203-4010-497d-8773-9b5c622a1372"],"dc:identifier.uri":["https://kclpure.kcl.ac.uk/portal/files/12371843/Studentthesis-Rowa_Alhabbab_2013.pdf"],"dc:language":["eng"],"dc:publisher.department":["Immunoregulation & Immune Intervention"],"dc:publisher.institution":["King's College London"],"dc:relation.isreferencedby":["https://kclpure.kcl.ac.uk/portal/en/studentTheses/c91e6203-4010-497d-8773-9b5c622a1372"],"dc:title":["The role of B cells in the amplification and in the regulation of transplant rejection."],"dc:type":["Thesis"],"dc:type.qualificationlevel":["Doctoral Thesis"],"dc:type.qualificationname":["Doctor of Philosophy"]},"updated_at":"2026-07-24T02:44:31Z"}