Limits...
A Small Molecule β2 Integrin Agonist Improves Chronic Kidney Allograft Survival by Reducing Leukocyte Recruitment and Accompanying Vasculopathy.

Khan SQ, Guo L, Cimbaluk DJ, Elshabrawy H, Faridi MH, Jolly M, George JF, Agarwal A, Gupta V - Front Med (Lausanne) (2014)

Bottom Line: A CD11b agonist leukadherin-1 (LA1) increases leukocyte adhesion, preventing their transmigration and tissue recruitment in vivo.Serum creatinine levels showed significantly improved kidney function in LA1-treated mice compared to CsA-treated allograft controls [0.52 ± 0.18 mg/dL vs 0.24 ± 0.07 mg/dL (n = 5), respectively].These findings indicate a crucial role for CD11b/CD18 in the control of leukocyte migration to the transplanted kidney and identify integrin agonist LA1 as a novel potential therapeutic agent for kidney transplantation.

View Article: PubMed Central - PubMed

Affiliation: Department of Internal Medicine, Rush University Medical Center , Chicago, IL , USA.

ABSTRACT
Kidney allograft rejection is associated with infiltration of inflammatory CD11b+ leukocytes. A CD11b agonist leukadherin-1 (LA1) increases leukocyte adhesion, preventing their transmigration and tissue recruitment in vivo. Here, we test the extent to which LA1-mediated activation of CD11b/CD18 enhances kidney allograft survival in a mouse model of fully MHC-mismatched orthotopic kidney transplantation, where C57BL/6J (H-2(b)) recipients received kidney allografts from Balb/c mice (H-2(d)). Isograft control recipients received a kidney from a littermate. Control isograft and allograft recipients were treated daily with cyclosporine (CsA) for 2 weeks, while the test group received CsA therapy and daily LA1 injections during week 1 and alternate days during weeks 2-8. LA1 treatment reduced interstitial leukocyte infiltration in the allograft, reduced neointimal hyperplasia and glomerular damage, and prolonged graft survival from 48.5% (CsA only) to 100% (CsA and LA1) on day 60. Serum creatinine levels showed significantly improved kidney function in LA1-treated mice compared to CsA-treated allograft controls [0.52 ± 0.18 mg/dL vs 0.24 ± 0.07 mg/dL (n = 5), respectively]. Furthermore, combination therapy reduced macrophage infiltration and increased the frequency of FoxP3 + Tregs in the allograft. These findings indicate a crucial role for CD11b/CD18 in the control of leukocyte migration to the transplanted kidney and identify integrin agonist LA1 as a novel potential therapeutic agent for kidney transplantation.

No MeSH data available.


Related in: MedlinePlus

LA1 treatment prolongs transplant survival and increases kidney function. (A) A flow diagram describing the mouse model of chronic allograft nephropathy utilized in this study. (B) Schematic representing the timeline of treatment with CsA and/or LA1 and the allogeneic kidney transplant surgery as described in the Section “Concise Methods.” The chemical structure of LA1 is also shown on the top. (C) A Kaplan–Meier plot of graft survival for isografts (non-filled circles, n = 3) or allografts treated with either CsA alone (triangles, n = 4) or a combination of CsA and LA-1 (squares, n = 5) over time (in weeks). Significance was determined using the Log-rank (Mantel–Cox) test. **P < 0.01 (D) A plot showing LC-MS/MS-based quantification of serum creatinine levels in various samples at the indicated time points. Whole blood was collected at the indicated time points via retro-orbital puncture from experimental animals from isograft group (non-filled circles) or allograft groups treated with either CsA alone (triangles) or a combination of CsA and LA-1 (squares). Data shown are mean ± SEM (n = 5/group). Significance was determined using a two-tailed Student’s t-test and the calculated P-value is shown. *P < 0.05.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
getmorefigures.php?uid=PMC4291902&req=5

Figure 2: LA1 treatment prolongs transplant survival and increases kidney function. (A) A flow diagram describing the mouse model of chronic allograft nephropathy utilized in this study. (B) Schematic representing the timeline of treatment with CsA and/or LA1 and the allogeneic kidney transplant surgery as described in the Section “Concise Methods.” The chemical structure of LA1 is also shown on the top. (C) A Kaplan–Meier plot of graft survival for isografts (non-filled circles, n = 3) or allografts treated with either CsA alone (triangles, n = 4) or a combination of CsA and LA-1 (squares, n = 5) over time (in weeks). Significance was determined using the Log-rank (Mantel–Cox) test. **P < 0.01 (D) A plot showing LC-MS/MS-based quantification of serum creatinine levels in various samples at the indicated time points. Whole blood was collected at the indicated time points via retro-orbital puncture from experimental animals from isograft group (non-filled circles) or allograft groups treated with either CsA alone (triangles) or a combination of CsA and LA-1 (squares). Data shown are mean ± SEM (n = 5/group). Significance was determined using a two-tailed Student’s t-test and the calculated P-value is shown. *P < 0.05.

Mentions: LA1 administration reduces leukocyte recruitment and kidney injury in a model of anti-GBM nephritis (45). Furthermore, LA1 treatment provided significant protection of WT B6 mice from renal ischemia-reperfusion injury (IRI) (Figure S1 in Supplementary Material). These data suggest that LA1 has significant reno-protective effects in an acute setting. Next, we investigated the efficacy of LA1 on kidney allograft function and survival. As previously described (9), the left kidney in the recipient C57BL/6J animal was removed and was replaced with a donor Balb/c kidney and the animals (n = 4-5 per group) were treated with CsA for 2 weeks post transplantation to prevent acute allograft rejection (Figures 2A,B). The native right kidney was removed 1 week later. Kidney function and graft survival was monitored in animals for up to 8 weeks post-transplantation, as described in the Section “Concise Methods.” One group of animals (LA1 group) were treated intraperitoneally (i.p.) with LA1 (2.5 mg/kg) daily for 1 week and every other day for the remaining weeks until the end of the study (2–8 weeks post-transplantation). The isograft control group comprised C57BL/6J (H-2b) recipients that received a kidney from a C57BL/6J (H-2b) littermate. Recipient survival is significantly reduced in this model, with a measureable decline in kidney function beginning at 3 weeks post-transplantation (9). The results show that approximately 50% of CsA-treated animals were lost during the 8 weeks of the experiment due to loss of the transplanted allograft, whereas all animals with isografts survived (Figure 2C). Surprisingly, CsA + LA1-treated animals showed 100% survival and graft protection. Serum creatinine levels indicated significantly improved kidney function in LA1-treated mice compared to allograft controls treated with CsA (0.52 ± 0.18 mg/dL of creatinine for CsA group vs 0.24 ± 0.07 mg/dL for CsA + LA1 group at end-point, Figure 2D). Similarly, urinary analysis showed a much higher level of proteinuria in the CsA only treated animals versus the CsA + LA1 group (11.7 ± 6.6 mg/mg of albumin/creatinine for CsA group vs 3.6 ± 0.4 mg/mg for CsA + LA1 group at end-point).


A Small Molecule β2 Integrin Agonist Improves Chronic Kidney Allograft Survival by Reducing Leukocyte Recruitment and Accompanying Vasculopathy.

Khan SQ, Guo L, Cimbaluk DJ, Elshabrawy H, Faridi MH, Jolly M, George JF, Agarwal A, Gupta V - Front Med (Lausanne) (2014)

LA1 treatment prolongs transplant survival and increases kidney function. (A) A flow diagram describing the mouse model of chronic allograft nephropathy utilized in this study. (B) Schematic representing the timeline of treatment with CsA and/or LA1 and the allogeneic kidney transplant surgery as described in the Section “Concise Methods.” The chemical structure of LA1 is also shown on the top. (C) A Kaplan–Meier plot of graft survival for isografts (non-filled circles, n = 3) or allografts treated with either CsA alone (triangles, n = 4) or a combination of CsA and LA-1 (squares, n = 5) over time (in weeks). Significance was determined using the Log-rank (Mantel–Cox) test. **P < 0.01 (D) A plot showing LC-MS/MS-based quantification of serum creatinine levels in various samples at the indicated time points. Whole blood was collected at the indicated time points via retro-orbital puncture from experimental animals from isograft group (non-filled circles) or allograft groups treated with either CsA alone (triangles) or a combination of CsA and LA-1 (squares). Data shown are mean ± SEM (n = 5/group). Significance was determined using a two-tailed Student’s t-test and the calculated P-value is shown. *P < 0.05.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4291902&req=5

Figure 2: LA1 treatment prolongs transplant survival and increases kidney function. (A) A flow diagram describing the mouse model of chronic allograft nephropathy utilized in this study. (B) Schematic representing the timeline of treatment with CsA and/or LA1 and the allogeneic kidney transplant surgery as described in the Section “Concise Methods.” The chemical structure of LA1 is also shown on the top. (C) A Kaplan–Meier plot of graft survival for isografts (non-filled circles, n = 3) or allografts treated with either CsA alone (triangles, n = 4) or a combination of CsA and LA-1 (squares, n = 5) over time (in weeks). Significance was determined using the Log-rank (Mantel–Cox) test. **P < 0.01 (D) A plot showing LC-MS/MS-based quantification of serum creatinine levels in various samples at the indicated time points. Whole blood was collected at the indicated time points via retro-orbital puncture from experimental animals from isograft group (non-filled circles) or allograft groups treated with either CsA alone (triangles) or a combination of CsA and LA-1 (squares). Data shown are mean ± SEM (n = 5/group). Significance was determined using a two-tailed Student’s t-test and the calculated P-value is shown. *P < 0.05.
Mentions: LA1 administration reduces leukocyte recruitment and kidney injury in a model of anti-GBM nephritis (45). Furthermore, LA1 treatment provided significant protection of WT B6 mice from renal ischemia-reperfusion injury (IRI) (Figure S1 in Supplementary Material). These data suggest that LA1 has significant reno-protective effects in an acute setting. Next, we investigated the efficacy of LA1 on kidney allograft function and survival. As previously described (9), the left kidney in the recipient C57BL/6J animal was removed and was replaced with a donor Balb/c kidney and the animals (n = 4-5 per group) were treated with CsA for 2 weeks post transplantation to prevent acute allograft rejection (Figures 2A,B). The native right kidney was removed 1 week later. Kidney function and graft survival was monitored in animals for up to 8 weeks post-transplantation, as described in the Section “Concise Methods.” One group of animals (LA1 group) were treated intraperitoneally (i.p.) with LA1 (2.5 mg/kg) daily for 1 week and every other day for the remaining weeks until the end of the study (2–8 weeks post-transplantation). The isograft control group comprised C57BL/6J (H-2b) recipients that received a kidney from a C57BL/6J (H-2b) littermate. Recipient survival is significantly reduced in this model, with a measureable decline in kidney function beginning at 3 weeks post-transplantation (9). The results show that approximately 50% of CsA-treated animals were lost during the 8 weeks of the experiment due to loss of the transplanted allograft, whereas all animals with isografts survived (Figure 2C). Surprisingly, CsA + LA1-treated animals showed 100% survival and graft protection. Serum creatinine levels indicated significantly improved kidney function in LA1-treated mice compared to allograft controls treated with CsA (0.52 ± 0.18 mg/dL of creatinine for CsA group vs 0.24 ± 0.07 mg/dL for CsA + LA1 group at end-point, Figure 2D). Similarly, urinary analysis showed a much higher level of proteinuria in the CsA only treated animals versus the CsA + LA1 group (11.7 ± 6.6 mg/mg of albumin/creatinine for CsA group vs 3.6 ± 0.4 mg/mg for CsA + LA1 group at end-point).

Bottom Line: A CD11b agonist leukadherin-1 (LA1) increases leukocyte adhesion, preventing their transmigration and tissue recruitment in vivo.Serum creatinine levels showed significantly improved kidney function in LA1-treated mice compared to CsA-treated allograft controls [0.52 ± 0.18 mg/dL vs 0.24 ± 0.07 mg/dL (n = 5), respectively].These findings indicate a crucial role for CD11b/CD18 in the control of leukocyte migration to the transplanted kidney and identify integrin agonist LA1 as a novel potential therapeutic agent for kidney transplantation.

View Article: PubMed Central - PubMed

Affiliation: Department of Internal Medicine, Rush University Medical Center , Chicago, IL , USA.

ABSTRACT
Kidney allograft rejection is associated with infiltration of inflammatory CD11b+ leukocytes. A CD11b agonist leukadherin-1 (LA1) increases leukocyte adhesion, preventing their transmigration and tissue recruitment in vivo. Here, we test the extent to which LA1-mediated activation of CD11b/CD18 enhances kidney allograft survival in a mouse model of fully MHC-mismatched orthotopic kidney transplantation, where C57BL/6J (H-2(b)) recipients received kidney allografts from Balb/c mice (H-2(d)). Isograft control recipients received a kidney from a littermate. Control isograft and allograft recipients were treated daily with cyclosporine (CsA) for 2 weeks, while the test group received CsA therapy and daily LA1 injections during week 1 and alternate days during weeks 2-8. LA1 treatment reduced interstitial leukocyte infiltration in the allograft, reduced neointimal hyperplasia and glomerular damage, and prolonged graft survival from 48.5% (CsA only) to 100% (CsA and LA1) on day 60. Serum creatinine levels showed significantly improved kidney function in LA1-treated mice compared to CsA-treated allograft controls [0.52 ± 0.18 mg/dL vs 0.24 ± 0.07 mg/dL (n = 5), respectively]. Furthermore, combination therapy reduced macrophage infiltration and increased the frequency of FoxP3 + Tregs in the allograft. These findings indicate a crucial role for CD11b/CD18 in the control of leukocyte migration to the transplanted kidney and identify integrin agonist LA1 as a novel potential therapeutic agent for kidney transplantation.

No MeSH data available.


Related in: MedlinePlus