Breaking barriers-Suppressing revolt
While immunity is intrinsically designed to protect the self against foreign antigens, in the era of transplantation – allograft or xenograft, whole organ or stem cells – a deliberate attempt is made to suppress immune pathways that would reject the transplant. The barrier to tolerating the graft is broken by suppressing the expected revolt by cellular and humoral immunity, enabling successful survival and functional engraftment. The rare possibility of the donor being a twin of course obviates the possibility of rejection. To begin with blood group and HLA cross-matching reduce the possibility of graft survival by minimizing key donor antigens that the donor or recipient APCs will present to the T-cells to. In contemporary practice, renal transplantation is most frequent and well established, followed by liver, heart, pancreas and others. Iatrogenic immunosuppression with a host of drugs targeting immune pathways, has a cost: a lifelong follow-up to monitor rejection- hyperacute, acute and chronic; usual and unusual opportunistic infections with morbid and mortal outcomes and, appearance of neoplasia of certain types unique to the transplantation setting, often triggered by activation of oncogenic viruses. A full account of these can be found in standard textbooks and review articles: some suggestions are placed at the end of this post.
Insights and Impact
- Transplant medicine has been enabled by advances in Immunology, preventative tissue cross-match, surgical techniques and pharmacotherapies for immunosuppression
- Long term complications of rejection, opportunistic infections and neoplastic outcomes remain a challenge
- This branch of medicine, encompassing multiple disciplines, provides opportunity for cutting edge research both in growing organs in the lab from non-human sources and refining molecular tissue matches
- Active community engagement has targeted donor empanelment, through creating registries of individuals committed to the humanitarian mission of volunteering their own organs or giving willingness for donation on their own death or brain death of healthy kin
- Ethical considerations and related legal frameworks govern the availability of organs to control commercial exploitation or criminal misuse playing on the desperation of patients and families awaiting a transplant
Rhythm ’n rhyme
Making strange bedfellows
Sometimes Immunity’s a curse when it looks a gift horse in the mouth
Identifies allografts as foreign: T-cells and antibodies make a transplant go South;
In direct alloantigen recognition, donor APC’s induce recipient T cells to reject
Donor HLA and other antigens seen as foreign: transplant survival becomes suspect;
In indirect alloantigen recognition, recipient APC’s do just the same
Recipient T-cells, antibodies rise to the occasion: united, they announce: end-game!
Hyperacute kidney rejection’s immediate, preformed antibodies wreck graft endothelial cells:
Glomerular and arteriolar thrombosis, cortical infarction, cast a deathly spell;
Weeks or months later Acute rejection may rear its ugly head
CD8+ CTLs, CD4+ helper cells in cell-mediated rejection, tubulitis-endotheliitis wed;
C4d and antibody deposition confirm antibody-mediated rejection capillaritis is in force
Increasing immunosuppression may permit the graft to run its course;
Chronic rejection is heralded when interstitial fibrosis and graft arteriosclerosis appear
T-cell cytokines stimulate fibroblast-vascular smooth muscle proliferation, costing graft life dear;
Steroids, mycophenolate, tacrolimus, manifold T-cell suppressing options
Pooled intravenous IgG, plasmapheresis, to counteract humoral pathways, a concoction;
In renal transplant reactivation of BK polyoma virus, in HSC CMV infections may surface
Immunosuppression risks oncogenic virus activation, related-neoplasia may win the race;
A miracle of 20th century Medicine, solid organ and HSC transplantation has endured
Underpinned by advances in Immunology, tissue matching, surgical skills, ethics: all on board;
Kidney, marrow, lung, heart, liver, pancreas transplants, the spectrum is on the rise
Allografts – cadaveric and live - now established, genetically modified xenografts ready to opportunity prise;
The challenge remains for the recipient’s immunity to tolerate a donor allograft
For the physician to balance immunosuppression to reduce rejection versus opportunistic infections going daft...
Deep Dive
A. Mechanisms of Transplant rejection reactions
Acknowledgement – https://step1.medbullets.com/immunology/105053/transplant
Q. Which of the three types of rejection is most amenable to modulating immunosuppression as a means of graft survival?
B. Immunosuppression-associated infections in Hematopoietic stem cell transplantation patients
Acknowledgement – https://obgynkey.com/opportunistic-infections-in-hematopoietic-stem-cell-transplantation/
DIY. Analyze the difference in approach to the diagnosis and treatment of these infections in the immunocompromised compared to immunocompetent patients
Read on:
- Mangum DS, Caywood E. A clinician’s guide to HLA matching in allogeneic hematopoietic stem cell transplant. Hum Immunol. 2022 Oct;83(10):687-694. doi: 10.1016/j.humimm.2022.03.002. Epub 2022 Mar 25. PMID: 35346535.
- https://banfffoundation.org/central-repository-for-banff-classification-resources-3/
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