(NIH.gov)
7 Nov. 2018. Proteins known to regulate immune cells, given as nanoscale particles, are shown in lab mice to encourage long-term acceptance of a transplanted heart. A team from Mount Sinai medical school in New York describes its findings in yesterday’s issue of the journal Immunity (paid subscription required).
Heart transplants are performed for people with heart failure, where other treatments are not working and will not be helped by other solutions, such as ventricular assist devices, or mechanical heart pumps. One of the key risks of a heart transplant is the immune system’s rejection of the donated heart. Immune system rejection is triggered by myeloid cells, considered the first-responders of the innate immune system that recognize invading tissue and alert T-cells, the cells that fight off invading pathogens and foreign tissue.
Rejection of donated hearts and other organs can be controlled with drugs that suppress the immune system, but these drugs can put people at risk for infections and some cancers, and require transplant recipients to take many medications for the rest of their lives. Most immunosuppressive drugs work by inhibiting T-cells. The team led by Mount Sinai cancer specialist Jordi Ochando and radiologist Willem Mulder are seeking a different approach to blocking rejection, by preventing myeloid cells from triggering T-cell responses against the donated organ.
Their solution uses proteins known to recognize and trigger myeloid cells, dectin-1 and toll like receptor 4, or TLR4. Ochando, Mulder, and colleagues formulated these proteins as nanoscale particles, where 1 nanometer equals 1 billionth of a meter. The researchers combined the first set of proteins with a complementary protein, also in nanoparticle form, called TRAF6 that inhibits co-stimulation of the immune system, in effect blocking the myeloid triggers. The protein nanoparticles are then combined with high-density lipoprotein, the so-called good cholesterol that carries clot-forming cholesterol through the blood stream to the liver.
The Mount Sinai team tested the protein nanoparticles in lab mice with transplanted hearts, which were given no other immune-system suppressing drugs. The results show the protein nanoparticles alone blocked the myeloid cells from triggering immune reactions to the transplanted organs, so that 75 percent of the mice accepted the transplanted hearts without rejection for 100 days. Mice receiving heart transplants but no drugs of any kind rejected the transplants within 10 days, while mice with transplants and immune-system suppressing drugs rejected the transplanted organs within 50 days.
“Our findings and the development of a novel nano-immunotherapy platform represent a revolutionary approach to prevent organ transplant rejection,” says Ochando in a Mount Sinai statement.”If this can be successfully translated to the clinic, this may eliminate the need for lifelong, continuous immunosuppressive medication and provide a promising solution for successful organ transplantation.”
Mulder adds that, “It’s a completely different approach that can be employed to other conditions that are characterized by maladaptive trained immunity, such as autoimmune and cardiovascular diseases.”
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