Graft-Versus-Leukemia Effect in Minor Antigen Mismatched Chimeras Given Delayed Donor Leucocyte Infusion: Immunoregulatory Aspects and Role of Donor T and Asgm1-Positive Cells1

Sefrioui, Hassan; Billiau, An; Waer, Mark

doi:10.1097/00007890-200007270-00020

Cited by 18 publications

(25 citation statements)

References 29 publications

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“…They were weighed and scored for GVHD weekly. Signs of GVHD typically observed in this model are weight loss, ruffled fur, hunched posture, diarrhea and lethargy, 4,30,31 in accordance with other mouse models of GVHD. 32 On the basis of the published clinical GVHD scores, each parameter was scored as follows: 0 ¼ normal, 1 ¼ mild, 2 ¼ moderate and 3 ¼ severe.…”

Section: Assessment Of Gvhdsupporting

confidence: 86%

CTLA-4 blockade in murine bone marrow chimeras induces a host-derived antileukemic effect without graft-versus-host disease

et al. 2007

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We studied the effect of CTLA-4 blockade on graft-versusleukemia and graft-versus-host responses in a mouse model of minor histocompatibility-mismatched bone marrow transplantation. Early CTLA-4 blockade induced acute graft-versus-host disease. Delayed CTLA-4 blockade resulted in a lethal condition with lymphosplenomegaly, but with stable mixed T-cell chimerism, unchanged alloreactive T-cell frequencies and absent anti-host reactivity in vitro. In contrast, multiorgan lymphoproliferative disease with autoimmune hepatitis and circulating anti-DNA auto-antibodies were documented. Splenic lymphocytes exhibited ex vivo spontaneous proliferation and a marked proliferative response against host-type dendritic cells pulsed with syngeneic (host-type) tissue-peptides. Both phenomena were exclusively mediated by host and not donor T cells, supporting an autoimmune pathogenesis. Selectively hostderived T-cell immune reactivity was equally documented against leukemia-peptide-pulsed dendritic cells, and this was paralleled by a strong in vivo antileukemic effect in anti-CTLA-4-treated and subsequently leukemia-challenged chimeras. In conclusion, delayed CTLA-4 blockade induced a host-derived antileukemic effect, occurring in the context of an autoimmune syndrome and strictly separated from graft-versus-host disease. Both antileukemic and autoimmune responses depended on the allogeneic component, as neither effect was seen after syngeneic bone marrow transplantation. Our findings reveal the potential of using CTLA-4 blockade to establish antileukemic effects after allogeneic hematopoietic stem cell transplantation, provided autoimmunity can be controlled.

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Section: Assessment Of Gvhdsupporting

confidence: 86%

CTLA-4 blockade in murine bone marrow chimeras induces a host-derived antileukemic effect without graft-versus-host disease

et al. 2007

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“…In a selected experiment, we included a group of mice treated with donor lymphocyte infusion and leukemia challenge, and confirm previous studies, 16,18 the DLI-challenged group showed 66% long-term survival after leukemia challenge ( Figure 2). …”

Section: Recipient Lymphocyte Infusion Induces a Late-onset And Partisupporting

confidence: 58%

“…This chimerism evolution is in contrast with the rapid conversion from mixed to full donor chimerism following donor lymphocyte infusion in the same experimental model 18 and with strong lymphohematopoietic alloreactivity generally seen in patients after donor lymphocyte infusion therapy. [4][5][6][7][8] We postulate that following lethal irradiation, infused healthy donor bone marrow cells have a competitive advantage over residual host-type bone marrow cells and that adoptively transferred donor lymphocytes reinforce this effect, leading to a rapid conversion from mixed to full donor chimerism.…”

Section: Discussionmentioning

confidence: 77%

Recipient lymphocyte infusion in MHC-matched bone marrow chimeras induces a limited lymphohematopoietic host-versus-graft reactivity but a significant antileukemic effect mediated by CD8+ T cells and natural killer cells

Somer¹,

Sprangers²,

Fevery³

et al. 2010

Haematologica

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BackgroundChallenge of MHC-mismatched murine bone marrow chimeras with recipient-type lymphocytes (recipient lymphocyte infusion) produces antileukemic responses in association with rejection of donor chimerism. In contrast, MHC-matched chimeras resist eradication of donor chimerism by recipient lymphocyte infusion. Here, we investigated lymphohematopoietic host-versus-graft reactivity and antileukemic responses in the MHC-matched setting, which is reminiscent of the majority of clinical transplants. Design and MethodsWe challenged C3H→AKR radiation chimeras with AKR-type splenocytes (i.e. recipient lymphocyte infusion) and BW5147.3 leukemia cells. We studied the kinetics of chimerism using flowcytometry and the mechanisms involved in antileukemic effects using in vivo antibodymediated depletion of CD8 + T and NK cells, and intracellular cytokine staining. ResultsWhereas control chimeras showed progressive evolution towards high-level donor T-cell chimerism, recipient lymphocyte infusion chimeras showed a limited reduction of donor chimerism with delayed onset and long-term preservation of lower-level mixed chimerism. Recipient lymphocyte infusion chimeras nevertheless showed a significant survival benefit after leukemia challenge. In vivo antibody-mediated depletion experiments showed that both CD8 + T cells and NK cells contribute to the antileukemic effect. Consistent with a role for NK cells, the proportion of IFN-γ producing NK cells in recipient lymphocyte infusion chimeras was significantly higher than in control chimeras. ConclusionsIn the MHC-matched setting, recipient lymphocyte infusion elicits lymphohematopoietic hostversus-graft reactivity that is limited but sufficient to provide an antileukemic effect, and this is dependent on CD8 + T cells and NK cells. The data indicate that NK cells are activated as a bystander phenomenon during lymphohematopoietic T-cell alloreactivity and thus support a novel type of NK involvement in anti-tumor responses after post-transplant adoptive cell therapy.Key words: recipient lymphocyte infusion, antileukemic effect, CD8 T cells, NK cells. Citation: De Somer L, Sprangers B, Fevery S, Rutgeerts O, Lenaerts C, Boon L, Waer M, and Billiau AD. Recipient lymphocyte infusion in MHC-matched bone marrow chimeras induces a limited lymphohematopoietic host-versus-graft reactivity but a significant antileukemic effect mediated by CD8+ T cells and natural killer cells. Haematologica 2011;96(3):424-431. doi:10.3324/haematol.2010 This is an open-access paper. Recipient lymphocyte infusion in MHC-

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“…15,16 Similarly, in animal models of allo BMT, donor lymphocytes (DLs) can be safely infused, once a sufficient time interval after transplantation has elapsed. [17][18][19][20][21][22][23] Moreover, in murine bone marrow (BM) chimeras, DLI did induce distinct GVL effects. 17,21,22 These and other clinical and experimental data indicate that, whereas GVH and GVL responses may share effector cells and target antigens, the GVL effect may be dissociated from GVHD.…”

Section: Introductionmentioning

confidence: 99%

“…In this model, GVHD was avoided when DLI was delayed for 3 weeks after BMT while a distinct GVL response was allowed to develop. 21 In the present study, DLI was performed at different time points after BMT, as from the moment that DLI was previously shown to be safe. 21 The capacity of DLs to induce a GVL response was studied and was related to the degree of pre-existing chimerism and to the extent to which DLs were able to elicit alloreactivity in vivo and in vitro.…”

Section: Introductionmentioning

confidence: 99%

Crucial role of timing of donor lymphocyte infusion in generating dissociated graft-versus-host and graft-versus-leukemia responses in mice receiving allogeneic bone marrow transplants

Billiau

Fevery

Rutgeerts

et al. 2002

Blood

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A murine model of minor histocompatibility antigen-mismatched bone marrow transplantation (BMT) was used to study the role of timing of donor lymphocyte infusion (DLI) in eliciting graft-versushost (GVH) and graft-versus-leukemia (GVL) reactivity. We gave DLI at weeks 3 and 12 after BMT and related its ability to induce a GVL effect with (1) evolution of T cell chimeric status and (2) the extent to which DLI could elicit lymphohematopoietic GVH (LHGVH) reactivity. All mice remained free of GVH disease, but only week 3 DLI chimeras exhibited a significant GVL response when challenged with host-type leukemia cells. In these week 3 DLI chimeras, host-reactive T cells were found to proliferate in vivo (5-[and-6]-carboxyfluorescein diacetate, succinimidyl esther [CFSE]-labeled DLI inocula, TCR-V␤6 ؉ T-cell frequency) and T-cell chimerism rapidly converted from mixed into complete donor type, indicating the occurrence of LHGVH reactivity. In week 12 chimeras, DLI elicited none of the activities noted at week 3. Yet, in both instances, splenocytes, recovered following DLI, generated an equally strong antihost proliferative response in a mixed lymphocyte reaction, thereby arguing against a decisive role of regulatory cells. The lack of in vivo LHGVH reactivity after week 12 DLI was associated with a substantially increased level of pre-existing host-type T-cell chimerism. We conclude that elicitation of a GVL effect may require LHGVH reactivity and that the reason why timing of DLI was critical for obtaining LHGVH reactivity and the desired GVL effect may lie in the evolution of chimeric status. A possible direct involvement of residual host-type antigen-presenting cells in eliciting LHGVH reactivity after DLI should be studied using models that allow chimerism analysis in non-T-cell

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Graft-Versus-Leukemia Effect in Minor Antigen Mismatched Chimeras Given Delayed Donor Leucocyte Infusion: Immunoregulatory Aspects and Role of Donor T and Asgm1-Positive Cells1

Cited by 18 publications

References 29 publications

CTLA-4 blockade in murine bone marrow chimeras induces a host-derived antileukemic effect without graft-versus-host disease

CTLA-4 blockade in murine bone marrow chimeras induces a host-derived antileukemic effect without graft-versus-host disease

Recipient lymphocyte infusion in MHC-matched bone marrow chimeras induces a limited lymphohematopoietic host-versus-graft reactivity but a significant antileukemic effect mediated by CD8+ T cells and natural killer cells

Crucial role of timing of donor lymphocyte infusion in generating dissociated graft-versus-host and graft-versus-leukemia responses in mice receiving allogeneic bone marrow transplants

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