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IL-2 pathway blocking in combination with anti-CD154 synergistically establishes mixed macrochimerism with limited dose of bone marrow cells and prolongs skin graft survival in mice.

Lee JH, Ha J, Kim SH, Kim SJ - J. Korean Med. Sci. (2006)

Bottom Line: In graft versus host disease model using CFSE staining, CD4+ T cell and CD8+ T cell proliferation were reduced in groups treated with CTLA4-Ig or anti-IL-2R or both in combination with anti-CD154.However, anti-IL-2R was not so strong as CTLA4-Ig in terms of inhibition of T cell proliferation.In conclusion, IL-2 pathway blocking combined with anti-CD154 can establish macrochimerism with limited dose of BM transplantation and induce specific tolerance to allograft.

View Article: PubMed Central - PubMed

Affiliation: Department of Surgery, Hallym University College of Medicine, Chuncheon, Korea.

ABSTRACT
To facilitate the establishment of mixed chimerism with limited dose of bone marrow (BM) cells, and to achieve tolerance in skin graft model, combined blocking of costimulatory pathway and IL-2 pathway was used in minimally myeloablative model using busulfan. BM cells (2.5x10(7)) of BALB/c were injected into C57BL/6 mice at day 0 with full thickness skin graft after single dose injection of busulfan (25 mg/kg) on day-1. Recipients were grouped and injected the anti-CD154, CTLA4-Ig, anti-IL-2R at days 0, 2, 4, and 6 according to protocol. Mixed macrochimerism were induced in groups treated with anti-CD154+anti-CTLA4-Ig, anti-CD154+anti-IL-2R, and anti-CD154+anti-CTLA4 Ig+anti-IL-2R. Three groups having chimerism enjoyed prolonged graft survival more than 6 months. Superantigen deletion study revealed deletion of alloreactive T cells in combined blockade treated groups. In graft versus host disease model using CFSE staining, CD4+ T cell and CD8+ T cell proliferation were reduced in groups treated with CTLA4-Ig or anti-IL-2R or both in combination with anti-CD154. However, anti-IL-2R was not so strong as CTLA4-Ig in terms of inhibition of T cell proliferation. In conclusion, IL-2 pathway blocking combined with anti-CD154 can establish macrochimerism with limited dose of BM transplantation and induce specific tolerance to allograft.

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Related in: MedlinePlus

Survival of skin allografts. Combined use of costimulation blockade achieved indefinite graft survival. Groups are allogeneinc bone marrow transplantation with busulfan only (△; n=6), treated with anti-CD154 (□; n=4), anti-CD154 and anti-IL-2R (○; n=5), anti-CD154 and CTLA4-Ig (■; n=8), anti-CD154, anti-IL-2R and CTLA-4 Ig (●; n=8).
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Figure 2: Survival of skin allografts. Combined use of costimulation blockade achieved indefinite graft survival. Groups are allogeneinc bone marrow transplantation with busulfan only (△; n=6), treated with anti-CD154 (□; n=4), anti-CD154 and anti-IL-2R (○; n=5), anti-CD154 and CTLA4-Ig (■; n=8), anti-CD154, anti-IL-2R and CTLA-4 Ig (●; n=8).

Mentions: Donor specific allograft survival was observed using skin graft to see if chimeric animal accept graft without rejection. In group I, which received bone marrow only, could not prolong graft survival (median survival time [MST], 11 days). Anti-CD154 alone prolonged graft survival modestly (MST, 21 days), however, all the grafts failed eventually with limited dose of bone marrow. On the contrary, graft survival of group III, IV and V, to which anti-IL-2R or CTLA4-Ig or both were added, showed graft survival of more than 6 months (Fig. 2). Anti-IL-2R alone could not prolong graft survival and rejected rapidly as in control group in preliminary experiment (data not shown).


IL-2 pathway blocking in combination with anti-CD154 synergistically establishes mixed macrochimerism with limited dose of bone marrow cells and prolongs skin graft survival in mice.

Lee JH, Ha J, Kim SH, Kim SJ - J. Korean Med. Sci. (2006)

Survival of skin allografts. Combined use of costimulation blockade achieved indefinite graft survival. Groups are allogeneinc bone marrow transplantation with busulfan only (△; n=6), treated with anti-CD154 (□; n=4), anti-CD154 and anti-IL-2R (○; n=5), anti-CD154 and CTLA4-Ig (■; n=8), anti-CD154, anti-IL-2R and CTLA-4 Ig (●; n=8).
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC2721919&req=5

Figure 2: Survival of skin allografts. Combined use of costimulation blockade achieved indefinite graft survival. Groups are allogeneinc bone marrow transplantation with busulfan only (△; n=6), treated with anti-CD154 (□; n=4), anti-CD154 and anti-IL-2R (○; n=5), anti-CD154 and CTLA4-Ig (■; n=8), anti-CD154, anti-IL-2R and CTLA-4 Ig (●; n=8).
Mentions: Donor specific allograft survival was observed using skin graft to see if chimeric animal accept graft without rejection. In group I, which received bone marrow only, could not prolong graft survival (median survival time [MST], 11 days). Anti-CD154 alone prolonged graft survival modestly (MST, 21 days), however, all the grafts failed eventually with limited dose of bone marrow. On the contrary, graft survival of group III, IV and V, to which anti-IL-2R or CTLA4-Ig or both were added, showed graft survival of more than 6 months (Fig. 2). Anti-IL-2R alone could not prolong graft survival and rejected rapidly as in control group in preliminary experiment (data not shown).

Bottom Line: In graft versus host disease model using CFSE staining, CD4+ T cell and CD8+ T cell proliferation were reduced in groups treated with CTLA4-Ig or anti-IL-2R or both in combination with anti-CD154.However, anti-IL-2R was not so strong as CTLA4-Ig in terms of inhibition of T cell proliferation.In conclusion, IL-2 pathway blocking combined with anti-CD154 can establish macrochimerism with limited dose of BM transplantation and induce specific tolerance to allograft.

View Article: PubMed Central - PubMed

Affiliation: Department of Surgery, Hallym University College of Medicine, Chuncheon, Korea.

ABSTRACT
To facilitate the establishment of mixed chimerism with limited dose of bone marrow (BM) cells, and to achieve tolerance in skin graft model, combined blocking of costimulatory pathway and IL-2 pathway was used in minimally myeloablative model using busulfan. BM cells (2.5x10(7)) of BALB/c were injected into C57BL/6 mice at day 0 with full thickness skin graft after single dose injection of busulfan (25 mg/kg) on day-1. Recipients were grouped and injected the anti-CD154, CTLA4-Ig, anti-IL-2R at days 0, 2, 4, and 6 according to protocol. Mixed macrochimerism were induced in groups treated with anti-CD154+anti-CTLA4-Ig, anti-CD154+anti-IL-2R, and anti-CD154+anti-CTLA4 Ig+anti-IL-2R. Three groups having chimerism enjoyed prolonged graft survival more than 6 months. Superantigen deletion study revealed deletion of alloreactive T cells in combined blockade treated groups. In graft versus host disease model using CFSE staining, CD4+ T cell and CD8+ T cell proliferation were reduced in groups treated with CTLA4-Ig or anti-IL-2R or both in combination with anti-CD154. However, anti-IL-2R was not so strong as CTLA4-Ig in terms of inhibition of T cell proliferation. In conclusion, IL-2 pathway blocking combined with anti-CD154 can establish macrochimerism with limited dose of BM transplantation and induce specific tolerance to allograft.

Show MeSH
Related in: MedlinePlus