STTT | The team of Academician Wang Fusheng found that the infusion of human umbilical cord mesenchymal stem cells is safe and reliable to treat AIDS patients

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Although iNature combined antiretroviral therapy (ART) effectively controlled HIV replication, about 10-40% of HIV-1 treated patients failed to achieve normalization of CD4+ T counts, and were called "immune non-responders" (INR )
.

Compared with immune responders, such patients have a higher risk of morbidity and mortality
.

On June 9, 2021, the team of Academician Wang Fusheng from the Fifth Medical Center of the Chinese People’s Liberation Army General Hospital published an online publication entitled "Human umbilical cord mesenchymal stem cell transfusion in immune non-responders with" on Signal Transduction and Targeted Therapy (IF=13.
49).
AIDS: a multicenter randomized controlled trial" research paper, which designed this multicenter, randomized, double-blind, placebo-controlled, dose-determined phase II clinical trial of hUC-MSC infusion for HIV-1 INR patients
.

The primary endpoint is to assess the immune recovery of CD4 counts after transfusion of human umbilical cord mesenchymal stem cells (hUC-MSC)
.

The secondary endpoint is to check the changes in CD8 count and CD4/CD8 ratio, and confirm the safety of hUC-MSC blood transfusion
.

From May 2013 to March 2016, 72 patients with INR infected with HIV participated in this phase II randomized, double-blind, multicenter, placebo-controlled, dose-determining trial (NCT01213186)
.

They were assigned to receive high-dose (1.
5 × 10^6/kg body weight) or low-dose (0.
5 × 10^6/kg body weight) hUC-MSC, or placebo
.

Their clinical and immunological parameters were monitored in a 96-week follow-up study
.

The study found that hUC-MSC treatment is safe and well tolerated
.

Compared with the baseline, after 48 weeks of treatment, the CD4+ T counts of the high-dose group (P <0.
001) and low-dose group (P <0.
001) increased statistically, but there was no change in the control group
.

Kaplan-Meier analysis showed that compared with the control group, the low-dose group had a higher cumulative probability of getting an immune response (95.
8% vs.
70.
8%, P = 0.
004)
.

However, no significant changes in CD4/CD8+ T count and CD4/CD8 ratio were observed in the three groups
.

In short, hUC-MSC treatment is safe
.

However, the efficacy of hUC-MSC therapy in improving immune reconstitution in INR patients still needs to be further studied in a large cohort study
.

Although combined antiretroviral therapy (ART) has effectively controlled HIV replication, about 10-40% of HIV-1 treated patients fail to achieve normalization of CD4+ T counts, and are referred to as “insufficient immune responses” and “immune "Inconsistent responders", or "immune non-responders" (INR)
.

Compared with immune responders, such patients have a higher risk of morbidity and mortality
.

The possible mechanisms of INR include reduced bone marrow hematopoiesis, insufficient thymus output, residual virus replication, and abnormal immune activation, which ultimately leads to reduced CD4 production and excessive CD4 destruction
.

 ART, ART enhancement, immunomodulators (such as vitamin D, interleukin 2, interleukin 7), immunosuppressive agents, and probiotics have been used to promote the immune recovery of CD4 in HIV-1 INR patients.
Obtain satisfactory clinical benefits
.

Mesenchymal stem cells (MSC) are adult stem cells that can be derived from bone marrow, adipose tissue, placenta, umbilical cord, cord blood, peripheral blood, and liver
.

MSCs have considerable therapeutic effects due to their migration, differentiation, immune regulation and regeneration capabilities
.

Many published research reports claim that MSCs have been successfully used to treat different diseases, such as acute severe graft-versus-host disease (GVHD), heart failure, liver damage, osteoarthritis, autoimmune diseases and liver cirrhosis
.

Previously, it was found that hUC-MSC blood transfusion is safe, can reduce systemic immune overactivation, increase the initial circulation and central memory CD4 T cell count, and restore HIV-1 specific interferon (IFN)-γ and IL-2 in INR Produced
.

However, only 7 patients were included, and there were no dose escalations
.

Recently, Trujillo-Rodríguez et al.
used human allogeneic mesenchymal stromal cells infused from adipose tissue to treat patients with INR and reported no effect on improving immune recovery or reducing immune activation or inflammation in these patients
.

However, only five patients were selected
.

Therefore, the study designed this multicenter, randomized, double-blind, placebo-controlled, dose-determined phase II clinical trial of hUC-MSC infusion for HIV-1 INR patients
.

The primary endpoint is to assess the immune recovery of CD4 counts after hUC-MSC transfusion
.

The secondary endpoint is to check the changes in CD8 count and CD4/CD8 ratio, and confirm the safety of hUC-MSC blood transfusion
.

From May 2013 to March 2016, 72 patients with INR infected with HIV participated in this phase II randomized, double-blind, multicenter, placebo-controlled, dose-determining trial (NCT01213186)
.

They were assigned to receive high-dose (1.
5 × 10^6/kg body weight) or low-dose (0.
5 × 10^6/kg body weight) hUC-MSC, or placebo
.

Their clinical and immunological parameters were monitored in a 96-week follow-up study
.

The study found that hUC-MSC treatment is safe and well tolerated
.

Compared with the baseline, after 48 weeks of treatment, the CD4+ T counts of the high-dose group (P <0.
001) and low-dose group (P <0.
001) increased statistically, but there was no change in the control group
.

 Kaplan-Meier analysis showed that compared with the control group, the low-dose group had a higher cumulative probability of getting an immune response (95.
8% vs.
70.
8%, P = 0.
004)
.

However, no significant changes in CD4/CD8+ T count and CD4/CD8 ratio were observed in the three groups
.

In short, hUC-MSC treatment is safe
.

However, the efficacy of hUC-MSC therapy in improving immune reconstitution in INR patients still needs to be further studied in a large cohort study
.

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