Limits...
Cellular and molecular immune profiles in renal transplant recipients after conversion from tacrolimus to sirolimus.

Gallon L, Traitanon O, Sustento-Reodica N, Leventhal J, Ansari MJ, Gehrau RC, Ariyamuthu V, De Serres SA, Alvarado A, Chhabra D, Mathew JM, Najafian N, Mas V - Kidney Int. (2014)

Bottom Line: While tacrolimus-maintained patients showed a decrease in indirect alloreactivity over time post transplant, sirolimus conversion increased indirect alloreactive T-cell frequencies compared with tacrolimus-maintained patients.No histological differences were found in graft biopsies, but molecular profiles showed activation of the antigen presentation, IL-12 signaling, oxidative stress, macrophage-derived production pathways, and increased inflammatory and immune response in sirolimus-converted patients.Despite the molecular profile being favorable to calcineurin inhibitor-based regimen, there was no impact in renal function over 30 months of follow-up.

View Article: PubMed Central - PubMed

Affiliation: 1] Comprehensive Transplant Center, Northwestern University, Chicago, Illinois, USA [2] Department of Medicine-Nephrology, Northwestern University, Chicago, Illinois, USA.

ABSTRACT
Tacrolimus and sirolimus are commonly used maintenance immunosuppressants in kidney transplantation. As their effects on immune cells and allograft molecular profiles have not been elucidated, we characterized the effects of tacrolimus to sirolimus conversion on the frequency and function of T cells, and on graft molecular profiles. Samples from renal transplant patients in a randomized trial of 18 patients with late sirolimus conversion and 12 on tacrolimus maintenance were utilized. Peripheral blood was collected at 0, 6, 12, and 24 months post randomization, with T-cell subpopulations analyzed by flow cytometry and T-cell alloreactivity tested by IFN-γ ELISPOT. Graft biopsy samples obtained 24 months post randomization were used for gene expression analysis. Sirolimus conversion led to an increase in CD4(+)25(+++)Foxp3(+) regulatory T cells. While tacrolimus-maintained patients showed a decrease in indirect alloreactivity over time post transplant, sirolimus conversion increased indirect alloreactive T-cell frequencies compared with tacrolimus-maintained patients. No histological differences were found in graft biopsies, but molecular profiles showed activation of the antigen presentation, IL-12 signaling, oxidative stress, macrophage-derived production pathways, and increased inflammatory and immune response in sirolimus-converted patients. Thus, chronic immune alterations are induced after sirolimus conversion. Despite the molecular profile being favorable to calcineurin inhibitor-based regimen, there was no impact in renal function over 30 months of follow-up.

No MeSH data available.


Related in: MedlinePlus

Percentage of CD3 T cells, CD4 T cells, CD8 T cells, effector CD4 T cells (CD4+CD25−), naïve CD4 T cells (CD4+CD45RA+), memory CD4 T cells (CD4+CD45RO+), naïve CD8 T cells (CD8+CD45RA+) and memory CD8 T cells (CD8+CD45RO+) in PBMC (Mean ± SD) at baseline, 6 months, 12 months and 24 months post-randomization comparing between TAC maintained and SRL converted group. SRL conversion did not result in changes of these T cell subpopulations. TAC, Tacrolimus maintained group; SRL Sirolimus converted group.
© Copyright Policy
Related In: Results  -  Collection


getmorefigures.php?uid=PMC4382402&req=5

Figure 3: Percentage of CD3 T cells, CD4 T cells, CD8 T cells, effector CD4 T cells (CD4+CD25−), naïve CD4 T cells (CD4+CD45RA+), memory CD4 T cells (CD4+CD45RO+), naïve CD8 T cells (CD8+CD45RA+) and memory CD8 T cells (CD8+CD45RO+) in PBMC (Mean ± SD) at baseline, 6 months, 12 months and 24 months post-randomization comparing between TAC maintained and SRL converted group. SRL conversion did not result in changes of these T cell subpopulations. TAC, Tacrolimus maintained group; SRL Sirolimus converted group.

Mentions: Frequency of total CD3+, CD4+, CD8+, CD4+CD25−, naïve(CD4+CD45RA+) and memory(CD4+CD45RO+) CD4 T cells, naïve(CD8+CD45RA+) and memory(CD8+CD45RO+) CD8 T cells and Treg (CD4+CD25+++FOXP3+) in peripheral blood were analyzed by flow cytometry. Changes in T cells subpopulations and Treg were compared over time from baseline to 6-, 12- and 24-months post-randomization within each group and between TAC and SRL groups. As shown in Figure 2A, frequencies and absolute numbers (cells/μl of blood) of Treg increased in the SRL group over time from baseline to 24-months post-randomization (0.41±0.20 (TAC) vs 0.32±0.28 (SRL) CD4+CD25+++FOXP3+ cells/ul of blood at baseline (p=0.89) compared to 0.60±0.18 (TAC) vs 1.33±0.28 (SRL) CD4+CD25+++FOXP3+ cells/ul of blood at 24-months (p=0.01). However the frequencies of CD4+, CD8+, CD4+CD25− T cells, naïve and memory CD4 and CD8 T cells remained unchanged (Figure 3).


Cellular and molecular immune profiles in renal transplant recipients after conversion from tacrolimus to sirolimus.

Gallon L, Traitanon O, Sustento-Reodica N, Leventhal J, Ansari MJ, Gehrau RC, Ariyamuthu V, De Serres SA, Alvarado A, Chhabra D, Mathew JM, Najafian N, Mas V - Kidney Int. (2014)

Percentage of CD3 T cells, CD4 T cells, CD8 T cells, effector CD4 T cells (CD4+CD25−), naïve CD4 T cells (CD4+CD45RA+), memory CD4 T cells (CD4+CD45RO+), naïve CD8 T cells (CD8+CD45RA+) and memory CD8 T cells (CD8+CD45RO+) in PBMC (Mean ± SD) at baseline, 6 months, 12 months and 24 months post-randomization comparing between TAC maintained and SRL converted group. SRL conversion did not result in changes of these T cell subpopulations. TAC, Tacrolimus maintained group; SRL Sirolimus converted group.
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC4382402&req=5

Figure 3: Percentage of CD3 T cells, CD4 T cells, CD8 T cells, effector CD4 T cells (CD4+CD25−), naïve CD4 T cells (CD4+CD45RA+), memory CD4 T cells (CD4+CD45RO+), naïve CD8 T cells (CD8+CD45RA+) and memory CD8 T cells (CD8+CD45RO+) in PBMC (Mean ± SD) at baseline, 6 months, 12 months and 24 months post-randomization comparing between TAC maintained and SRL converted group. SRL conversion did not result in changes of these T cell subpopulations. TAC, Tacrolimus maintained group; SRL Sirolimus converted group.
Mentions: Frequency of total CD3+, CD4+, CD8+, CD4+CD25−, naïve(CD4+CD45RA+) and memory(CD4+CD45RO+) CD4 T cells, naïve(CD8+CD45RA+) and memory(CD8+CD45RO+) CD8 T cells and Treg (CD4+CD25+++FOXP3+) in peripheral blood were analyzed by flow cytometry. Changes in T cells subpopulations and Treg were compared over time from baseline to 6-, 12- and 24-months post-randomization within each group and between TAC and SRL groups. As shown in Figure 2A, frequencies and absolute numbers (cells/μl of blood) of Treg increased in the SRL group over time from baseline to 24-months post-randomization (0.41±0.20 (TAC) vs 0.32±0.28 (SRL) CD4+CD25+++FOXP3+ cells/ul of blood at baseline (p=0.89) compared to 0.60±0.18 (TAC) vs 1.33±0.28 (SRL) CD4+CD25+++FOXP3+ cells/ul of blood at 24-months (p=0.01). However the frequencies of CD4+, CD8+, CD4+CD25− T cells, naïve and memory CD4 and CD8 T cells remained unchanged (Figure 3).

Bottom Line: While tacrolimus-maintained patients showed a decrease in indirect alloreactivity over time post transplant, sirolimus conversion increased indirect alloreactive T-cell frequencies compared with tacrolimus-maintained patients.No histological differences were found in graft biopsies, but molecular profiles showed activation of the antigen presentation, IL-12 signaling, oxidative stress, macrophage-derived production pathways, and increased inflammatory and immune response in sirolimus-converted patients.Despite the molecular profile being favorable to calcineurin inhibitor-based regimen, there was no impact in renal function over 30 months of follow-up.

View Article: PubMed Central - PubMed

Affiliation: 1] Comprehensive Transplant Center, Northwestern University, Chicago, Illinois, USA [2] Department of Medicine-Nephrology, Northwestern University, Chicago, Illinois, USA.

ABSTRACT
Tacrolimus and sirolimus are commonly used maintenance immunosuppressants in kidney transplantation. As their effects on immune cells and allograft molecular profiles have not been elucidated, we characterized the effects of tacrolimus to sirolimus conversion on the frequency and function of T cells, and on graft molecular profiles. Samples from renal transplant patients in a randomized trial of 18 patients with late sirolimus conversion and 12 on tacrolimus maintenance were utilized. Peripheral blood was collected at 0, 6, 12, and 24 months post randomization, with T-cell subpopulations analyzed by flow cytometry and T-cell alloreactivity tested by IFN-γ ELISPOT. Graft biopsy samples obtained 24 months post randomization were used for gene expression analysis. Sirolimus conversion led to an increase in CD4(+)25(+++)Foxp3(+) regulatory T cells. While tacrolimus-maintained patients showed a decrease in indirect alloreactivity over time post transplant, sirolimus conversion increased indirect alloreactive T-cell frequencies compared with tacrolimus-maintained patients. No histological differences were found in graft biopsies, but molecular profiles showed activation of the antigen presentation, IL-12 signaling, oxidative stress, macrophage-derived production pathways, and increased inflammatory and immune response in sirolimus-converted patients. Thus, chronic immune alterations are induced after sirolimus conversion. Despite the molecular profile being favorable to calcineurin inhibitor-based regimen, there was no impact in renal function over 30 months of follow-up.

No MeSH data available.


Related in: MedlinePlus