Thymus Organoids Restore Immune Function in Mice

Researchers here demonstrate restoration of immune function in mice via transplant of tissue engineered thymus-like organoids, one of a number of lines of research that aims to restore thymic function to boost the aging immune system. A sizable part of the age-related decline of the adaptive immune system arises from a problem of supply: there are no longer enough naive T cells to mount an effective response to new threats.

Some potential approaches to solving this problem involve dealing with issues that reduce the naive T cell population, while others focus on increasing the supply of new T cells. The thymus plays a vital role in the generation of new T cells, and is very active in early life, but withers away upon reaching adulthood in a process known as thymic involution, reducing the supply of immune cells to a trickle. Thus placing new thymic tissue with youthful characteristics into old individuals should be a way to generate more T cells - a straightforward transplant works, for example:

One of the major obstacles in organ transplantation is to establish immune tolerance of allografts. Although immunosuppressive drugs can prevent graft rejection to a certain degree, their efficacies are limited, transient, and associated with severe side effects. Induction of thymic central tolerance to allografts remains challenging, largely because of the difficulty of maintaining donor thymic epithelial cells in vitro to allow successful bioengineering.

Here, the authors show that three-dimensional scaffolds generated from decellularized mouse thymus can support thymic epithelial cell survival in culture and maintain their unique molecular properties. When transplanted into athymic nude mice, the bioengineered thymus organoids effectively promoted homing of lymphocyte progenitors and supported thymopoiesis. Nude mice transplanted with thymus organoids promptly rejected skin allografts and were able to mount antigen-specific humoral responses on immunization. Notably, tolerance to skin allografts was achieved by transplanting thymus organoids constructed with either thymic epithelial cells coexpressing both syngeneic and allogenic major histocompatibility complexes, or mixtures of donor and recipient thymic epithelial cells.

Our results demonstrate the technical feasibility of restoring thymic function with bioengineered thymus organoids and highlight the clinical implications of this thymus reconstruction technique in organ transplantation and regenerative medicine.

Link: http://www.ncbi.nlm.nih.gov/pubmed/25903472

Comments

No lifespan extension in the mice receiving the transplant?

Posted by: Daniel Lemire at July 10th, 2015 2:28 PM

@Daniel Lemire: I'd assume the authors didn't check, since it wasn't a point of interest for them, and running a life span study is hugely expensive in comparison to running a study that only looks at immediate results.

Posted by: Reason at July 10th, 2015 3:22 PM

If you could create a thymus with both donor and thymic epithelial cells to prevent the creation of T cells that recognize the donor organ's MHCs... that would be a big win... and this has now been achieved in mice.

Maybe rather than just undergoing organ transplants, in the future people will also have their thymus removed and replaced with a tolerance enabling one.

Posted by: Jim at July 10th, 2015 4:59 PM

I'm also wondering if you could create non nude xenograft mice models with an immune system and human skin patch using a thymus with a mix of human donor and mouse epithelial cells?

Posted by: Jim at July 10th, 2015 5:30 PM

More directly would be to rejuvenate the stem cell niche in old organs such as the Thymus and allow the stem cells to repair the damage themselves. Irina Conboy has demonstrated this is possible in various tissues using TGF-Beta 1. It is perfectly possible to restore dormant stem cells to work in this manner. Also of note is TGF-beta 1 inhibits telomerase and thus leads to telomere loss too.

I look forward to progress in this field as so far Irina's method has worked in all tissues tested (brain, skin, muscle). It apparently rejuvenates the stem cell niche too which would then allow fresh stem cells to be implanted. I could see this being a viable way to regenerate and top up tissues and organs.

Posted by: Steve H at July 13th, 2015 7:58 AM

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