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Q.737. To what extent the Human leukocyte antigens (HLA) can be considered a roadmap for transplantation?

COVID-19 and solid organ transplant (SOT).

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COVID-19 poses new challenges for individual SOT candidates & transplant recipients (TR), as well as the process of SOT. There’s currently a theoretical risk of transmitting SARS-CoV-2 (virus responsible of COVID-19) from an organ donor to TR based upon detection of viral RNA particles in organs that can be transplanted (eg, lung, heart, kidney, intestine), despite donor-derived infection has not been observed to date. Owing to this risk with possibility of transmitting SARS-CoV-2 to health care providers, all solid organ donor and TR should be screened for COVID-19 by history, chest imaging & microbiologic testing. Post-tx, SOT recipients may be at increased risk for acquisition of COVID-19 as they’re immunocompromised (im/m) and have frequent contact with health care system, although this link has not been studied. Clinical pivture of COVID-19 in SOT recipients are variable and similar to that seen in non-im/m ptns. However, fever appears to be less common. Whether disease course is more severe is not known.  



Q.737. To what extent the Human leukocyte antigens (HLA) can be considered a roadmap for transplantation?      👉

HLA system: Synonymous é human mj. histocompatibility cx (MHC), wch describes a group of genes on chr. 6 that encode cell surface markers, Ag-presenting molecules. Classical MHC spans 3.6 Mb & incl. > 200 genes, many of which are not known to be involved in immune function. Identification of MHC-related genes outside these boundaries & findings of extended linkage disequilibrium hs led to the proposal: extended MHC, which spans 7.6 MB & has > 400 loci.  HLA region subdivided: class I, II & III. Each one has numerous gene loci, including: expressed genes, transcripts & pseudogenes. Some loci are highly polymorphic.

Class I contains: genes encoding class I HLA Ag., wch incl.: HLA A,B & C.. Class I Ag.s are expressed on all body cells, except RBCs & trophoblasts. They’re made up of a heavy chain (a chain) encoded within MHC, which combines noncovalently é the non-polymorphic light chain (B chain), also termed β2-microglobulin, wch’s encoded on chromosome 15, not in MHC, to form: final dimerized molecule.

Class II contains: HLA-DR, DQ & DP. Class II Ag. are constitutively expressed on B cells, dendritic cells & monocytes, and can be induced during inflmmation on many other cell types that normally have little or no expression. As é class I, class II molecules also consist of a (heavy) & B (light) chain. However, both chains are coded for by genes within MHC (HLA-DRA & DRB). DQ & DP Ag each hv polymerphic a &B chains, which can dimerize in various combinations; in contrast, DR dimers all share invariant a chain, while B chain carries the extreme polymorphism ch.ch..

Region betw. class I & II is known as 🠞class III. Although this region does not contain any of HLA genes, it does contain many important genes é immune response, incl.: several “complement” components (C2, C4 & f. B), several cytokines known to play in role in inflmmation pathways, e.g. TNF, lymphotoxin a & lymphotoxin B & a heat shock protein gene, HSP-70, tht encodes a chaperone molecule.

HLA types determination hs become much more accurate and led to frequent revision of n/c. Typing was initially performed by serology, then more specificities were detected by mixed lymphocyte typing using homozygous typing cells. Twomjor developed 🠞molecular based HLA typing & more stable n/c : (1) Determination of gene structure & sequence for HLA genes. (2) PCR technology. PCR hs provided the basis for convenient & rapid HLA typing, based upon the exact nucleotide sequences of individual alleles.  Many disease are ass. é classical HLA I & II genes, as well as é some of non-HLA genes in MHC region (eg, C4). Results among different ethnicities may vary, and definition of ptn. group may influence degrees of association. Attention should be given to statistical methods used when interpreting association studies.  Current data remain at the level of associations, not dis. mechanisms. Nevertheless, HLA associations which’re reproducible & robust provide important clues about development of certain disorders. A variety of models hv bn postulated to explain these associations functionally.

Q.738. How can you interpret transplantation immunobiology?     👓

A. Immune response involved in organ Tx. is a form of adaptive immunity, or one in wch the response is to a specific. Ag.. Principal targets of the immune are (MHC) molecules expressed é surface of donor cells (allo-MHC). 

T-cell recognition of Ag👈is the Iry event tht initiates immune resp.. This key step 🔑requires interaction of T-cell receptor é Ag presented as a peptide by Ag-presenting cell (APC) & costimulatory receptor/ligand interaction on T-cell/APC cell surface. Activated T-cells are directly cytotoxic and provide help for B cell A.B. production & macrophage-induced delayed type hypersensitivity responses. 

Proteins encoded by MHC are the “principal antigenic” determinants of graft Rj.. Organs transplanted betw. MHC identical individuals 😃are readily accepted, whereas organs transplanted between MHC Ag. mismatched ones are inevitably rejected 😌in abs. of im/m. ag.. Ag. presenting protein products of MHC have been classified into class I & II tht’re ch.ch. by structure, expression & cellular compartment fr. wch they obtain antigenic peptides to present to T-cells. Class I MHC including: HLA-A,-B &-C molecules & found on all cell types except RBCs. Class I present cytoplasm-derived peptide Ag to CD8 +ve T-cells wch induce cell lysis.

Class II incl.: HLA-DP, -DQ & -DR molecules. Class II are constituteively expressed on interstitial dendritic cells, macrophages & B cells but expression may be upregulated on epithelial cell & vsc. endothelial cell after exposure to proinflmm. cytokines. Class II present peptides derived fr. extracellular proteins to CD
4 +ve T-cells.  Activation of costimulatory pathways is required for T-cell entry into cell cycle. Multiple costimulatory molecules hv bn identified incl.: CD28 & CD40.

Leukocyte🐦migration” fr. circulation to site of inflmm. involves: (1) Selectin-mediated rolling. (2) Chemokine-mediated triggering. (3) Integrin-mediated firm adhesion. (4) PECAM- & chemokine-mediated transmigration. Chemokine-regulated attraction of leukocytes to sites of tissue injury, infection., or alloTx. is essential for induction of Ac. inflmmatory response. 

T helper cells are divided into 2 distinct populations, type 1 (Th1) & type 2 (Th2) cells. Th1 cells produce🠞[IL-2 & IFN-gamma & induce macrophage activation 🠞 DTH resp.. Ac. Allgraft Rj. is mainly mediated by Th1 immune response.  T-cell activation 🠞 intracellular signalling 🠞 activates cytokine DNA promoter regions🠞 permitting transcription of mRNA. AlloAg.-dependent & alloAg.-independent f.s contribute to the effecter mchanism underlying allgraft Rj. 😐

Dgx: similar to general population. As Sn & Sm of COVID-19 may be subtle in TR and disease progression can be rapid, some physicians hv a lower threshold for evaluating & testing TR. Approach to management (eg, antivirals, supportive care) is also similar to general population, although careful attention should be paid to possibility drug-drug interactions & effects on the im/m regimen. Adjustments to im/m protocol should be individualized, based according to disease severity, specific regimen used, type of organ transplant, time post-tx, and risk of acute allograft rejection. Some organ TR recover without reduction in im/m. that carries the risk of rejection & immune reconstitution. Conversely, continued im/m. may enhance the risk of uncontrolled infection.